Basic Pharmacokinetics

Basic Pharmacokinetics REV. 99.4.
25 -1
Copyright 1996-1999 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
F I R S T E D I T I O N
Basic Pharmacokinetics
Michael C. Makoid, Ph.D.
Professor of Pharmaceutical Sciences
Creighton University School of Pharmacy
and Allied Health Sciences,
Omaha, Nebraska
Phillip J. Vuchetich
Pharm.D. Candidate
Creighton University School of Pharmacy
and Allied Health Sciences,
Omaha, Nebraska
Umesh V. Banakar, Ph.D.
Professor of Pharmaceutical Sciences
St. Louis College of Pharmacy
St. Louis, Missouri
Basic Pharmacokinetics REV. 99.4.25 -2
Copyright 1996-1999 The Virtual University Press
All rights reserved.
ISBN 0-000-000000-0
ABCDEFGHIJ-DO-89
Acknowledgement
When I first started teaching, I had the good fortune to work with another new
Ph.D., John Cobby. We struggled through our first five years on the otherside of
the podium together and learned many of the tenents upon which this book is
based, not content but process. First and formost, it was his belief that students are
bright, enthusiastic and hardworking. We should tell them what to do and get out
of their way. We both prepared extensive handouts complete with even more
extensive practice problems so that the student could experience the scientific
method as a detective might solve a murder mystery. The idea was to make learn-
ing pharmaceutical science interesting and fun. Through the years, as the methods
became more refined, student perceptions and performance improved dramatically.
John ultimately abandoned academe to go to work in the real world of industry,
clearly their gain and our loss. I approached him some years ago to co-author this
text. He declined believing himself to be too far removed from the cutting edge of
this discipline. That may be true (I doubt it!), but what can not be argued is that he
was a major contributor to this book in his philosophy and class notes. Over the
years, the explainations were rewritten and revised. Many new problems were
added and some were suplanted. These teaching aides have evolved but their ori-
gins are clear. Using the industry standard regarding authorship, which defines an
author as one whose contributions significantly alters the content of the paper, Dr.
Cobby is an author of this book.
CHAPTER 1 Introduction
Basic Pharmacokinetics 1-2
Course Objectives: 1-3
Course Arrangement: 1-3
Learn the tools; get the pharmacokinetic parameters from patient information. 1-3
Learn the modifications of the pharmacokinetic parameters which result from illness. 1-5
Apply the tools; use the pharmacokinetic parameters to develop dosage regimens. 1-5
Apply the tools in specialized drug classes. 1-5
Exams 1-7
Library Assignment in Pharmacokinetics 1-7
Blooms taxonomy for the Hierarchy of Educational Objectives 1-9
Course Contract 1-10
Computers in the course 1-14
Survival Kit 1-15
Things for your Survival Kit! 1-15
What you will gain: (your goals) 1-16
Tentative Schedule 1-17
Study Group 1: Learn the tools - obtain pharmacokinetic parameters from data. 1-17
Study group 2: Learn how the parameters are modified. 1-19
Study Group 3: Apply the tools in compromised patients. 1-20
Study Group 4: Apply the tools in special cases. 1-20
Competency Statements Related To Pharmacokinetics 1-22
Specific Competency Statements addressed in this course 1-22
Pharmacokinetic Symbolism 1-25
Amount Terms (unit: mass) 1-25
Concentration terms (units mass/volume) 1-26
Volume Terms (unit: volume) 1-26
Time Terms (unit: time) 1-27
Rate Constant Terms (unit: reciprocal time (*), mass/time (**) 1-27
Clearance Terms (units: volume/time) 1-28
Rate Terms (units: mass/time (*), mass/time, volume (**), volume/time (***) 1-28
Other Terms 1-29
Subscripts 1-30
Superscripts 1-30
First Lesson in Pharmacokinetics 1-32
CHAPTER 2 Mathematics Review
Concepts of Mathematics 2-2
Mathematical Preparation 2-3
Zero and Infinity 2-3
Expressing Large and Small Numbers 2-3
Significant Figures 2-4
Rules of Indices 2-4
Logarithms 2-6
Natural Logarithms 2-6
Negative Logarithms 2-9
Using Logarithmic and Anti-logarithmic Tables 2-10
Dimensions 2-11
Dimensional Analysis 2-12
Calculus 2-14
Differential Calculus 2-14
Non-linear Graphs 2-14
Slope of Non-linear Graph 2-15
Value of the Slope 2-15
Differentiation from First Principles 2-16
Rule of Differentiation 2-17
Three Other Derivatives 2-17
A Seeming Anomaly 2-18
Integral Calculus 2-19
Rule of Integration 2-19
The Constant of Integration 2-20
The Exception to the Rule 2-20
A Useful Integral 2-20
Example Calculations 2-21
Graphs 2-24
Graphical Conventions 2-25
Straight Line Graphs 2-26
The Slope of a Linear Graph (m) 2-28
Linear Regression: Obtaining the slope of the line 2-29
Parallel lines 2-31
Graphical Extrapolations 2-32
Significance of the Straight Line 2-32
Graphical Honesty 2-32
Axes with Unequal Scales 2-33
Graphs of Logarithmic Functions 2-34
Semilogarithmic Coordinates 2-34
Log - Log Coordinates 2-38
Pitfalls of Graphing: Poor Technique 2-38
Graphical analysis 2-40
Pharmacokinetic Modeling 2-44
Making a Model 2-45
One Compartment Open Model 2-47
The LaPlace Transform 2-48
Table of LaPlace Transforms 2-49
Symbolism 2-49
Conventions used in drawing pharmacokinetic schema. 2-50
Steps for Integration Using the LaPlace Transform 2-53
Example Integration Using the LaPlace Transform 2-54
Second Example Integration Using the LaPlace Transform 2-56
Third Example Integration Using the LaPlace Transform 2-57
Conclusions 2-58
Table of LaPlace Transforms 2-60
LaPlace Transform Problems 2-62
LaPlace Transform Solutions 2-63
CHAPTER 3 Pharmacological Response
Pharmacological Response 3-2
The Hyperbolic Response Equation 3-2
Interrelationships between concentration, time and response 3-3
Change in Response with Time 3-4
One-Compartment Open Model: Intravenous Bolus Injection 3-4
One-Compartment Open Model: Oral Administration 3-4
Duration of Effective Pharmacological Response 3-4
Pharmacokinetic Parameters from Response Data 3-5
Delayed Response 3-5
Response of active metabolite: 3-6
Therapeutic Drug Monitoring 3-7
Therapeutic monitoring: Why do we Care? 3-9
Problems 3-11
Answers: Oxpranolol 3-18
Answers: Minoxidil 3-21
Answers: Propranolol 3-23
CHAPTER 4 I.V. Bolus Dosing
I.V. Bolus dosing of Parent compound 4-2
Plasma 4-2
Iv bolus, parent compound, plasma Problems 4-7
Urine 4-47
Metabolite 4-51
Plasma 4-51
Urine 4-56
CHAPTER 5 I.V. Infusion
Parent compound 5-2
Plasma 5-2
Problems 5-10
CHAPTER 6 Biopharmaceutical Factors
CHAPTER 7 Oral Dosing
Oral dosing 7-3
Valid equations: ( oral dosing, plasma) 7-3
Utilization 7-3
CHAPTER 8 Bioavailability, Bioequivalence, and Drug Selection
Bioavailability, Bioequivalence and Drug Product Selection 8-2
Relative and Absolute Bioavailability 8-2
Factors Influencing Bioavailability 8-4
Methods of Assessing Bioavailability 8-11
Study Design 8-15
In-vitro Dissolution and Bioavailability 8-15
In-vitro / in-vivo correlation studies- 8-18
Bioequivalence 8-20
Bioequivalence Regulations 8-23
Study Design 8-26
Assessment of bioequivalence 8-29
Controversies and Concerns in Bioequivalence 8-31
Generic Drugs and Product Selection 8-35
The Orange Book 8-38
Therapeutic equivalence 8-38
Therapeutic equivalence evaluation codes- 8-39
Drug Product Selection 8-44
Considerations in selecting a manufacturer 8-45
Special Cases 8-50
Summary 8-54
Questions 8-55
Answers to Questions 8-57
Bioavailibility Equations 8-58
Problems 8-60
Solutions 8-80
Caffeine on page 61 8-80
Cefetamet Pivoxil on page 62 8-83
Cefixime on page 63 8-86
Ceftibuten on page 64 8-87
Cimetidine on page 65 8-88
Diurnal Variability in Theophylline Bioavailability on page 66 8-89
cis-5-Fluoro-1-[2-Hydroxymethyl-1,3-Oxathiolan-5-yl] Cytosine (FTC) on page 67 8-90
Hydromorphone on page 68 8-91
Isosorbide Dinitrate on page 69 8-92
Ketanserin on page 70 8-93
Methotrexate on page 71 8-94
Moclobemide on page 72 8-95
Nalbuphine on page 73 8-96
Nefazodone on page 74 8-97
Ondansetron on page 75 8-98
Omeprazole on page 76 8-99
Paroxetine on page 77 8-100
Ranitidine on page 78 8-101
Sulpiride on page 79 8-102
References 8-103
CHAPTER 9 Clearance
Equations 9-2
Definitions and Terms 9-3
Measurement of Creatinine Clearance 9-4
Model Correlations 9-5
Renal Clearance 9-5
Systemic Clearance and Metabolic Clearance 9-5
Use in Pharmacokinetic Equations 9-6
Physiological Factors Affecting Clearance 9-7
Intrinsic Clearance 9-7
Extraction Ratio (E) 9-8
Hepatic Function and Clearance 9-10
Alterations in Hepatic blood Flow 9-10
Alterations in Hepatic Intrinsic Clearance 9-10
Tabulated or Graphical Alterations 9-11
Renal Function and Clearance 9-12
General Equations for Changes in Clearance 9-14
Plasma/Blood ratio 9-14
Half life and elimination rate constant in relationship to clearance 9-16
Effects of alterations in protein binding on clearance 9-16
Problems 9-17
CHAPTER 10 Dosage Regimen (Healthy, Aged, and Diseased Patients)
Therapeutic Drug Monitoring 10-2
Therapeutic Range 10-2
Therapeutic monitoring: Why do we Care? 10-4
Steady State 10-5
Diseases - Dosing the Compromised Patient 10-10
Problems 10-12
Answers 10-36
CHAPTER 11 Multicompartment Modeling
Executive Summary 11-2
Equations 11-3
PHARMCOKINETICS: MAMMILLARY MODELS 11-4
Begin 11-90
Problems 11-91
Two-compartment Model Equations 11-119
Answers 11-120
CHAPTER 12 Protein Binding
CHAPTER 13 Nonlinear (Michaelis-Menton) Kinetics
Problems 13-2
Nonlinear Equations 13-14
Answers 13-14
CHAPTER 14 Practice Exams: Section 1
Nifedipine - Section 1 3
Nifedipine Data 3
Nifedipine Questions 4
Nifedipine Solutions 6
Enalapril - Section 1 11
enalapril data 11
Enalapril Questions 13
enalapril Solutions 14
Ciprofloxacin Section 1 19
Ciprofloxacin data 19
Ciprofloxacin Questions 20
Ciprofloxacin Solutions 21
Methylphenidate Section 1 23
methylphenidate data 23
MethylPhenidate Questions: 24
methylPhenidate Solutions 25
Adinazolam - Section 1 27
ADINAZOLAM DATA 27
Adinazolam Questions 28
Adinazolam Solutions 30
Labetalol - Section 1 32
labetalol data 32
labetalol Questions 33
labetalol Solutions 34
Zidovudine Section 1 36
zidovudine data 36
Zidovudine Questions 38
Zidovuldine Solutions 40
Fosinopril Section 1 42
fosinopril data 42
Fosinopril Questions 44
Fosinopril Solutions 46
Omeprazole 49
Omeprazole Data 49
Omeprazole Questions 50
Omeprazole solutions 53
EXP3312, an Experimental Drug 57
EXP3312 DATA 57
EXP3312 & M1 Questions: 59
Graph Paper 62
CHAPTER 15 Practice Exams: Exam 2
Nifedipine: Exam 2 2
Nifedipine Questions: 3
Valproate: Exam 2 6
Valproate Questions 7
Valproate Solutions 10
Methyl phenidate 11
Methyl phenidate Questions: 12
Methyl phenidate Solutions: 13
Verapamil 15
Verapamil Questions 16
Verapamil Solutions 17
Hydromorphone hydrochloride 19
Hydromorphone hydrochloride Questions 20
Fosinopril Sodium 23
Fosinopril Questions 24
Fosinopril Sodium Solutions 26
Remoxipride 28
Remoxipride Questions 29
Remoxipride Solutions 31
Naproxen 33
Naproxen Questions 34
Naproxen Solutions 36
38
CHAPTER 16 Exam 3
Pharmacokinetics Final Exam 16-2
Basic Pharmacokinetics REV. 99.4.25 1-1
CHAPTER 1 Introduction
Author: Michael Makoid and John Cobby
Reviewer: Phillip Vuchetich
OBJECTIVES
At the completion of this chapter, the successful student shall be able to:
1. define pharmacokinetics
2. state the overall objectives of the course
3. state the major themes of the course
4. state the course organizational structure with respect to study sections
5. state the objectives of each study section
6. state the examination structure and objectives
7. state student performance expectations
8. state the schedule and timeline
Introduction
1.1 Basic Pharmacokinetics
What is pharmacokinet-
ics?
Pharmacokinetics is the mathematics of the time course of Absorption, Distribu-
tion, Metabolism, and Excretion (ADME) of drugs in the body. The biological,
physiological, and physicochemical factors which influence the transfer processes
of drugs in the body also influence the rate and extent of ADME of those drugs in
the body. In many cases, pharmacological action, as well as toxicological action, is
related to plasma concentration of drugs. Consequently, through the study of
pharmacokinetics, the pharmacist will be able to individualize therapy for the
patient.
Introduction
1.2 Course Objectives:
The Roman numerals refer to the cognitive complexity as described in Bloom's
Taxonomy of Educational Objectives described elsewhere in this document. At the
completion of this course, the successful student will be able to:
What will you be able to
do?
Calculate (III) patient and drug specific pharmacokinetic parameters from patient data,
Predict (calculate - III) the changes in relevant pharmacokinetic parameters in the patient with
selected diseases,
Utilize the above parameters to individualize patient therapy (devise a dosage regimen - V),
Communicate his/her therapy recommendations to another competent health professional (write
a consult - V).
1.2.1 COURSE ARRANGEMENT:
Two courses are described below. The first, a two credit (Creighton University
required) and the second, a three credit (CU optional) version. The two credit
course will consist of major themes one through three and exams one and two,
while the three credit course will add theme four and exam three. The four major
themes are entitled:
How is the course
arranged?
Learn the tools; get the pharmacokinetic parameters from patient information.
Learn the modifications of the pharmacokinetic parameters which result from illness.
Apply the tools; use the pharmacokinetic parameters to predict patient response and develop
dosage regimens for the normal as well as for the compromised patient.
Apply the tools in specialized drug classes.
Each major theme of the course is further broken down into study sections, each
with their own set of general objectives as shown below:
1.2.2 LEARN THE TOOLS; GET THE PHARMACOKINETIC PARAMETERS
FROM PATIENT INFORMATION.
A. Basic Mathematical skills objectives:
What will I be required
to be able to do? How
will examination ques-
tions be written for this
material?
1. Given a data set containing a pair of variables, the student will properly construct (III) var-
ious graphs of the data.
2. Given various graphical representations of data, the student will calculate (III) the slope
and intercept by hand as well as using linear regression.
3. The student shall be able to interpret (V) the meaning of the slope and intercept for the
various types of data sets.
4. The student shall demonstrate (III) the proper procedures of mathematical and algebraic
manipulations.
Introduction
5. The student shall demonstrate (III) the proper calculus procedures of integration and dif-
ferentiation.
6. The student shall demonstrate (III) the proper use of computers in graphical simulations
and problem solving.
7. Given the assumptions for the model, the student will construct (III) models of the ADME
processes using Laplace Transforms.
8. The student shall develop (V) integrated equations associated with the above models.
9. The student shall generate a pharmacokinetic model based on given information.
10. The student shall interpret a given model mathematically.
11. The student shall predict changes in the final result based on changes in variables through-
out the model.
B. Pharmacological Response objectives:
1. Given patient data of the following types, the student will be able to properly construct
(III) a graph and compute (III) the slope: response (R) vs. concentration (C), response (R)
vs. time (T), concentration (C) vs. time (T)
2. Given any two of the above data sets, the student will be able to compute (III) the slope of
the third.
C. IV one compartment model, plasma and urine objectives:
1. Given patient drug concentration and/or amount vs. time profiles, the student will calcu-
late (III) the relevant pharmacokinetic parameters available ( , K, , , , Clear-
ance, MRT) from IV data.
2. Given the appropriate pharmacokinetic parameters, the student shall simulate (III)
I.V. bolus/infusion dosing for parent compounds
Plasma concentration vs. time profile analysis
Rate vs. time profile analysis
3. Given patient specific pharmacokinetic parameters, the student shall provide professional
communication regarding IV bolus/infusion information
4. The student shall utilize computer aided instruction and simulation
5. Given patient drug concentration and/or amount vs. time profiles, the student will calcu-
late (III) the relevant metabolite (active vs. inactive) pharmacokinetic parameters avail-
able ( , K, , , , Clearance, MRT) from IV data.
D. Biopharmaceutical factor objectives: the student shall be able to discuss:
1. physiology and mechanisms of absorption
2. effects of diffusion, cardiac output / blood perfusion, physical properties of the drug and
body on distribution
3. biotransformation, first pass effect, and clearance
4. renal, biliary, mammary, salivary, other forms of excretion.
5. the effects of physiological changes with age, sex, and disease on the absorption, distribu-
tion, metabolism, and excretion of a drug.
E. Oral one compartment model objectives:
1. Given patient drug concentration and/or amount vs. Time profiles, the student will calcu-
late (III) the relevant pharmacokinetic parameters ( , K, , , , , Clearance,
MRT, MAT) available from oral data.
V
d
k
m
k
r
AUC
V
d
k
m
k
r
AUC
V
d
k
m
k
r
k
a
AUC
Introduction
F. Bioavailability objectives:
1. Given sufficient data to compare an oral product with another oral product or an IV prod-
uct, the student will estimate (III) the bioavailability (compare AUCs) and judge (VI) pro-
fessional acceptance of the product with regard to bioequivalence (evaluate (VI) AUC,
and ).
2. The student will write (V) a professional consult using the above calculations.
1.2.3 LEARN THE MODIFICATIONS OF THE PHARMACOKINETIC
PARAMETERS WHICH RESULT FROM ILLNESS.
G. Clearance objectives:
1. Given patient information regarding organ function, the student will calculate (III)
changes in clearance and other pharmacokinetic parameters inherent in compromised
patients.
1.2.4 APPLY THE TOOLS; USE THE PHARMACOKINETIC PARAMETERS
TO DEVELOP DOSAGE REGIMENS.
H. Dosage regimens objectives:
1. Given population average patient data, the student will devise (V) dosage regimens which
will maintain plasma concentrations of drug within the therapeutic range.
2. Given specific patient information, the patient will justify (VI) dosage regimen recom-
mendations.
3. Given patient information regarding organ function, the student will devise (V) and justify
(VI) dosage regimen recommendations for the compromised patient.
4. The student will write (V) a professional consult using the above calculations
1.2.5 APPLY THE TOOLS IN SPECIALIZED DRUG CLASSES.
I. Two Compartment Model objectives:
1. Given patient Concentration and/or Amount of Drug vs. Time, profiles the student will
calculate (III) the relevant pharmacokinetic parameters( , Alpha, , Beta, ,
, , , , Clearance, compartmental amount ratios) available from two com-
partment data.
2. Given population average patient data, the student will devise (V) a dosage regimen which
3. Given specific patient information, the patient will justify (VI) the optimal dosage regi-
men.
(VI) the optimal dosage regimen for the compromised patient.
T
p
C
p
( )
max
V
d1
A
1
B
1
k
10
k
12
k
21
AUC
Introduction
J. Protein Binding objective:
1. Given population average patient data, the student will devise (V) dosage regimens which
will maintain plasma concentrations of unbound drug within the therapeutic range.
men.
(VI) dosage regimens for the compromised patient.
K. Non-linear kinetics objective:
1. Given population average patient data, the student will devise (V) a dosage regimen which
men.
(VI) dosage regimens for the compromised patient.
Introduction
1.3 Exams
How are the exams
made?
Exams will consist of problems which will be linked directly back to an objective
(above) and a library assignment in which you will be asked to evaluate a research
article with the tools available to you by the time of the exam as discussed below.
1.3.1 LIBRARY ASSIGNMENT IN PHARMACOKINETICS
L. Library Assignment Objectives
What do I have to do in
the library?
1. Given a suitable primary research article in the area of pharmacokinetics, the student shall
calculate the pharmacokinetic parameters from the data using the tools learned in class.
2. The student shall communicate in writing the results of such calculations with suitable
commentary regarding differences and interpretations.
Format of the paper:
How should the paper
look?
1. Tell me what type of paper you have chosen to evaluate:
The problem sets show what data you need for each of these.
First Exam
What content should I
look for in the paper and
what is its relative
worth?
IV Bolus Parent compound 10 pts
IV Bolus Parent metabolite 12.5 pts
IV Infusion 12.5 pts
Pharmacological Response 15 pts
Second Exam
Oral Dosing / Bioavailability 10 pts
Third Exam (2 credit course)
Multiple dosing 10 pts
Clearance and disease 12.5 pts
Dosage Regimen 15 pts
Third Exam (3 credit course)
Two compartment model 10 pts
Protein Binding and Disease 12.5 pts
Non-linear kinetics and disease 15 pts
2. Include a Xerox copy of the entire paper. I need to evaluate it, too.
Introduction
3. Enlarge the graph by successive Xeroxes so that you can accurately evalu-
ate the data.
4. Do analysis of data by hand and by PKAnalyst, or Scientist.
5. Compare your work with the authors (short paragraph).
6. Comment on any differences of parameter calculation or interpretation. See
objectives above (Paragraph).
7. Write an exam question to obtain pharmacokinetic parameters. You know
from the first exam what they should look like.
Why do I need to do this
library assignment?
Each of the above sections is designed to bring the student an understanding of the
information and the processes necessary to operate as a competent professional in
the area of pharmacokinetic evaluation and consulting. Consequently, the
course will evolve from a quantitative, manipulative mathematics course to a
course which stresses communication skills. Consults will be graded not only on
content (the proper dosage regimen for the patient) but also grammar, punctuation,
spelling, organization and neatness. You may have the best medical information in
the world, but if it is poorly executed, it will be ignored.
Can I cram the night
before?
This course will probably be one of the more rigorous ones that you will have
experienced in your college career to date. It will be one of the first ones which
attempt to show some clinical relevance. The course can be successfully com-
pleted with your current skills and background. It is not difficult IF (and that is a
big IF) taken slowly, in small bites. Its just like eating an elephant - you can't do it
all in one sitting. Some of you may try to get it all the night before the exam,
regardless of my admonitions and those of your upper-class friends (ask them!). In
many cases, that has been more than sufficient to get A's and B's on exams in pre-
vious courses. Past experience tells many of you that you can do it. I suggest that
the requirements and expectations of a professional school are considerably more
than your undergraduate experience and it most likely will not work in many
courses which require assimilation of the information presented, as is expected in a
professional program.
Introduction
1.4 Blooms taxonomy for the Hierarchy of Educational Objectives
Blooms taxonomy for the Hierarchy of Educational Objectives describes the
expectations of a course in increasing order of complexity as:
What is cramming good
for? Lowest level of cog-
nitive skills.
I. To Know: means to memorize (recognize, recall) (Many college courses
require only this level of cognitive effort, hence the extensive experience with
multiple guess exams).
II. To Comprehend: means to translate; to be able to put information into your
own words. (Essay exams routinely call for this level of effort on the part of the
student).
This is where we begin. III. To Apply: means to be able to use knowledge, rules and principles in an
unfamiliar situation. (This is the lowest level of skill necessary to function at a
technician level).
This is where we need
to be in school.
IV. To Analyze: means to be able to critically examine a body of knowledge
and to be able to identify the relationships. (This is where a B.S. graduate should
operate. Education obviates the need for teachers.)
This is where we need
to be as graduates.
V. To Synthesize: means to put together information, not necessarily previ-
ously so organized, in order to get a new piece of information. (This is the begin-
ning level of professional judgment).
VI. To Evaluate: means to be able to judge the worth of an idea, form hypothe-
ses and do problem solving, research, invent new knowledge. (This is the doctoral
level of participation in the area).
Cant I just do it the
same way that I have
always studied?
A professional routinely operates at level IV and V with occasional forays into
level VI. This is where you will operate in this course and in most subsequent
courses in the professional curriculum. You will note that each of the objectives for
the course contains specific action words followed by the level in the taxonomy at
which you will operate. These are the standard descriptive terms for use in instruc-
tional objectives. You will be asked to do critical thinking, not simply recite or
recognize the right answer. Problems challenge thinking skills and demand the
synthesis of material into concepts. To facilitate this transition we both must work
very hard.
Introduction
1.5 Course Contract
I Will:
What will the teacher do
in this class? Act as a
facilitator.
1. Provide individualized learning methods: Some students learn by hearing
and others by seeing (auditory or visual learners). I have designed the course to
accommodate both types of learners. In class, I will provide you with executive
summaries of what you read. I will provide group leaders with detailed reviews of
materials for which they are responsible. I will tell you what I'm going to say, say
it, and then tell you what I said. I will also attempt to write it out and draw appro-
priate graphs, charts and pictures as well as appropriate visual aids in class and
with the homework problems. I will provide you with ample examples of the types
of manipulations that you will be expected to do. I will provide you with ample
problem sets so that you may practice those manipulations. I will provide you
with computer simulations so that you may see these manipulations in action and
begin to get a feel for the numbers and their magnitude. Feedback and interaction
is encouraged. If I am not meeting your perceived needs, you must tell me. Some
students might feel too intimidated to ask questions. To obviate this problem, you
will elect a group team leader, an ombudsman, whose job it will be to carry your
questions, concerns, and comments to me. It is your job and his responsibility to
see that the group interaction facilitates the learning process. This is not to prevent
you coming to see me but offered as another avenue of communication.
Will I learn anything rel-
evant in this course?
2. Provide clinical relevance to the practice of pharmacy. This will be stressed
at all times. I will also relate real clinical experiences; virtually all of the problems
come from real patients. Some educators believe examples must fit the theory
exactly. This gives the student a false set of reality parameters. Consequently,
when the data does not fall on the line the student rejects relevant information.
You will become familiar with real data, and the problems associated with real
data.
How will I know how Im
doing?
3. Give adequate feedback: Evaluation of your performance will be available
to you at all times. A running evaluation, updated weekly will be on my door for
your review. You may check any thing with me at any time. I expect that you will
see me outside of class time either individually if you need help or in supervised
review sessions. You must see me for assistance if your performance is unsatis-
factory.
What will the teacher be
doing? Engaging you in
an active learning pro-
cess.
4. Teach: As an operational definition this means: clarifying what you read,
demonstrating how and why things work as they do, and unifying the material -
attempting to generate the A - HA! syndrome. The correlate of teach from the stu-
dent view is learn. Neither is a passive process. I can not open your head and pour
the knowledge in. A saying in education is: Knowledge maketh a bloody
entrance. You must expend the effort necessary for you to learn.
Introduction
What must I do in this
active learning process?
You MUST participate in
class and in your
assigned groups!!!
5. Facilitate Learning. You received objectives (above) and a summary for
each study section (chapters in this text), of exactly what is expected of you with
examples in the problem sets at the end of each chapter. We will have ample time
during class to field questions generated by the correlated reading and problem
sets, as well as homework assignments. I will not be duplicating any book's efforts.
Student participation in class is required. You will answer (as well as ask) ques-
tions, do problems in class. You will sound things out and get feedback from me
and your fellow colleagues. Remember - the class is to help you learn. It is not the
sole means of learning, nor am I the source of all knowledge. Its only reason for
being is to help you organize and summarize what you learn. It has a relatively
simple plan with multiple examples. From these examples you will develop con-
cepts which will obviate the need for memorizing individual facts (or actually me
entirely). I will assist you in the formation of these concepts. It is patently obvious
that I can not give you every possible example of every type of question that you
will be asked during your professional career. For one thing I don't know what
questions you will be asked nor problems you will encounter. Going from the spe-
cific to the general forms concepts which will allow you to go from the general to
the specific, even if you have never been there before. The total medical knowl-
edge is now doubling at a rate of every 4 years. I can not teach you the content nec-
essary to operate 5 years in the future, let alone 40. You must learn to learn.
Hence, if you plan to become a competent professional, you must operate at least
in Bloom's level V.
How do I get in touch
with the teacher?
6. Be available: I do not have office hours. I believe them to be restrictive
from your view point. What I do have is a schedule prepared two weeks in advance
of when I am NOT available. You may set an appointment, at least a 1/2 day in
advance to guarantee that I see it, any other time. Of course, appointments are not
necessary if I'm in my office, but you take the chance of my not being there or
someone else being there ahead of you if you do not sign up. You may contact me
by e-mail: makoid@creighton.edu, or by phone: 402-280-2952.
How can I tell the
teacher how things are
going?
7. Be responsive: After each study section, you will be asked to provide me
with a one minute summary of the topic consisting answering the following ques-
tions:
a. What was the main thrust of the study section?
b. What was clear about the study section? What was done well?
c. What was unclear? How could it be done better?
This will provide me with a running monitor of my effectiveness as well as a
framework of what to stress and what to change.
Introduction
Do I have any say in the
examination questions?
After each exam, in addition to working out the problems, we will decide whether
any individual question was not covered by the objectives. Note: Not that it was
tough, not that you got it wrong, not that it didn't allow you to tell me what you
knew, but did I tell you that I was going to ask you to do it? (Was it covered by the
objectives?)
How are the exams
graded?
8) Evaluate your performance fairly and honestly: Quite simply, I'm going to tell
you what I expect that you will do. I will show you how to do it. I will provide you
with practice in doing it. I will provide you with an exam which tests your ability
to do it. The exams, as well as the whole course, will use real data and/or pharma-
cokinetic parameters for real drugs in real patient settings, much like the state
board exams (and hopefully real life). Like both of these situations, all answers are
interconnected. What that means is, if you improperly calculate a parameter which
is needed to make another calculation which is used to make a third, etc. ALL are
wrong. Conversely, if you can't get a particular calculation by one method or equa-
tion, try another. That's simply the way it is. You probably wouldn't get much sym-
pathy if you calculated a dosage regimen properly based on a wrong elimination
rate constant and ended up killing your patient.
You Will:
What do I have to do?
How much work is really
expected?
1) Come prepared to participate in class. This is your full time job. If you are
working full time, it is usually 40 to 60 hours per week. If you go to college 15 to
18 credits and prepare/study 2 hours for each credit, you work 45 to 55 hour per
week - you have a full time job. Your commitment is the 45 to 50 hour week not
just the contact hours and a night for each exam. This specifically means for each 1
hour class, I expect no less than 2 hours of preparation on your part. Each of you
will be assigned to a study group. You will work the problems together and teach
each other both in and out of class. We will have group discussion of class as well
as group problem solving. It will be your responsibility that every member of
your group be adequately prepared to answer for the group during recitation. There
will be a grade for group participation. Part of your grade will be based on quizzes,
how well your group performed both on the material for which you were responsi-
ble as well as overall and your peer evaluation.
Do I have to read the
text?
2) Read the text. When you read, read critically. Do you understand each idea?
Place a <+> (in pencil) in the left side of each paragraph after you read and under-
stand it. If you don't get it, place a <?> and come prepared to ask about it in class.
Why do I have to do the
problem sets?
3) Work the problems. Check the answers. These come from old exams, so they
are the type that you are likely to see. Work them in your study groups so that
everyone can see your thought processes. Bring them to class if you can not do
them or come and see me privately. Be prepared to show me your attempts at solv-
ing the problem. I will show you how to get started and give direction to your
thought. I will not work the problem for you. You would not learn if I did it for
you. It is crucial that you work the problems. Each has a specific objective. Over-
Introduction
all, they contribute to your gaining facility in the processes that a pharmacokineti-
cist must know how to do.
Can I just coast
through?
4) Do not delude yourself with respect to your performance. If you received a
grade that was less than satisfactory for you, do not simply console yourself by
saying I knew the stuff, I just made a little error. Can you get it right consis-
tently? That's when you know the stuff. That is not a laudable goal. That's what a
professional does. There have been several students in the past that knew that
stuff right up till the time that they had to repeat the course (and sometimes
beyond).
Introduction
1.6 Computers in the course
Can I get through with
just paper and pencil?
Computer literacy is necessary in this field. Consequently computers will pervade
the course. The homework problems (above) are to done both by hand and
checked with the computer. This will help your understanding of pharmacokinetics
in general and that homework objective in particular. Computers are natural
adjunctive tools in the teaching of pharmacokinetics. The are able to simulate the
concentration vs. time profiles and do difficult repetitive calculations which allow
the student to get a broad view of the processes involved.
What are the programs
that I will be using?
Programs that are currently being used in the course are The Scientist and PKAna-
lyst both from MicroMath Scientific Software, P.O. Box 71550, Salt Lake City, UT
84171-0550; or http://www.micromath.com. A working student version of the soft-
ware is available free for the downloading for your own work at home. A full
working version is on the Pharmacy Server.
In addition to the above course objectives, there are specific objectives for the use
of computers in the course. They are:
What will I be expected
to do with the comput-
ers?
1. Simulation. The student will construct a graph of the drug time course
using classical pharmacokinetics. The student will demonstrate effects of changes
in pharmacokinetic parameters on the ADME processes and correlated pharmaco-
logical / therapeutic response.
2. The student shall statistically evaluate models with regard to fit of data
using both linear and nonlinear regression analysis. The student will calculate
pharmacokinetic parameters which best describe the processes of ADME.
How can I use the com-
puters in the homework
and library questions?
These objectives will be met in a variety of ways. Clearly, the most direct method
is the solution of the problem sets by computer. First, I expect that you would do
the problem by hand, complete with graphs and other supporting calculations fol-
lowed by computer simulation and data analysis. Just how close did you come to
the best fit? Next, a portion of each exam will be a library exercise in which you
will find and evaluate a published article according to the principles that you
learned in class utilizing the computer facilities. How close did you come the
authors numbers? Do you, in fact, even agree with the authors? You will prepare a
short consult in which you describe the patient and what the authors did along with
your support (or non-support) of the authors conclusions.
Introduction
1.7 Survival Kit
1.7.1 THINGS FOR YOUR SURVIVAL KIT!
What do I need to buy
RIGHT NOW?
1. You will need a good calculator - One with and functions. You must
have it ASAP. You will use it in class.
2. You will also need 2 cycle semilog paper and a clear straight edge ruler for
use in class. These are available in the book store or at an office supply store.
3. You will need access to a computer (486 DX or higher). Micromath has
made available a student version of the programs for a nominal fee (This software
is pre-loaded in the Criss computer lab; you may purchase a copy for home use)
4. You will need a 3 D three-ring binder for collecting and maintaining all
the pages in this book as well as your class notes.
What do I need to do in
and out of class?
Work in your study groups. You never learn it so well as when you teach it to
someone else. Everyone benefits from a well run prepared study group. You are
not in competition with your fellow classmates. If everyone earns an A, then
everyone will receive one.
How can I organize this
material?
Organize and label your study notes. This is basic survival. This is one strategy
that I find works well. I recommend it highly. Good study notes are formatted on
loose-leaf in a three ring binder. The individual pages have a line drawn down
about 1/3 the way in. The notes are taken on the right (2/3) of the page, while
labels go in the left. The labels on the left are often written as questions, which are
answered in the text on the right. Loose leaf binders allow for the incorporation of
reading summaries as well as relevant problems and homework to be organized
with a divider all in one place. You should write intelligently, with proper punctua-
tion and spelling as if you were preparing a consult for a physician. Organization is
the key.
Remember: you may have all the information in the world at your fingertips; be
able to solve the most difficult therapy problem and no one will listen to you if you
can't communicate intelligently. Chapters in the book will be organized as above.
e
x
x ln
Introduction
1.7.2 WHAT YOU WILL GAIN: (YOUR GOALS)
How is the course to be
graded?
1. At the lowest level, a decent grade for a significant course. Specific grades
will be earned by attaining the following averages:
A 90 and above
B+ 85 to 89
B 80 to 84
C+ 75 to 79
C 70 to 74
D 60 to 69
F 59 and below
The number of exams and point distribution will be determined in class.
2. At the next higher level, I will guarantee that if you comprehend this mate-
rial at level V, you will have no trouble passing any state board anywhere with
regard to pharmacokinetics.
3. You will gain a useful skill that will make you an integral part of the health
care team.
Do I really need a
teacher to learn?
4 You will learn to learn. There is an old proverb which goes: Give a man a
fish and you feed him for a day. Teach a man to fish and you feed him for a life-
time. The B.S. Degree is designed to eliminate teachers. An educated man is one
who has learned to how to learn, not one who memorized a page in a book. That
is what you need to be a professional. The total medical knowledge is doubling at a
rate of every 3-4 years. That means that you will be out of date shortly after gradu-
ation (if not before) if you simply memorized content and don't learn to learn and
continue to learn throughout your career.
What about cheating? One last piece of information: Neither you nor I will not tolerate any academic
misconduct. Anyone caught will minimally receive an F for their efforts and I
will recommend dismissal from the program. The profession has no room for
unprofessional behavior. I will prosecute.
Introduction
1.8 Tentative Schedule
1.8.1 STUDY GROUP 1: LEARN THE TOOLS - OBTAIN PHARMACOKINETIC
PARAMETERS FROM DATA.
A: Introduction
1. Texts
2. Literature
3. Grading Policy
4. Course Philosophy
B: Math review
1. Numbers and exponents
2. Graphs and reaction order
3. Calculus
4. Laplace transform
5. Computer Introduction
6. Computer simulation and problem sets
C: Pharmacokinetic modeling
1. What a model is and what it isn't.
2. Why we model
3. Philosophy of modeling
D: Pharmacological Response
1. Michaelis - Menton Mass balance equation
2. Interrelationships between Concentration, time and response.
E: I.V. Bolus dosing
1. Parent compound
I. Plasma
a. Plasma concentration vs. time profile analysis
b. Computer aided instruction and simulation
c. Problem sets
d. Professional communication.
II Urine
a. Amount vs. time profile analysis
b. Rate vs. time profile analysis
c. Computer aided instruction and simulation
d. Problem sets
e. Professional communication.
2. Metabolite
Introduction
I. Plasma
c. Problem sets
II. Urine
a. Rate vs. time profile analysis
c. Problem sets
F: I.V. infusion
1. Parent compound
I. Plasma
c. Problem sets
II. Urine
d. Problem sets
1. Metabolite
I. Plasma
c. Problem sets
II. Urine
d. Problem sets
End of Material for first exam (six weeks for semester, two weeks for summer ses-
sion)
Introduction
1.8.2 STUDY GROUP 2: LEARN HOW THE PARAMETERS ARE MODIFIED.
G: Biopharmaceutical factors
1. Absorption
I. Physiology
II. Mechanisms
III. Physiological changes with age, sex, disease
2. Distribution
I. Diffusion
II. Cardiac output / blood perfusion
III. Physical properties of the drug
IV. Physical properties of the body
V. Physiological changes with age, sex, disease
3. Metabolism
I. Biotransformation methods
II. First pass effect
III. Clearance
IV. Physiological changes with age, sex, disease
4. Excretion
I. Renal
II. Biliary
III. Mammary
IV. Salivary
V. Misc.
VI. Physiological changes with age, sex, disease
H: Oral dosing
1. Parent compound
I. Plasma
c. Problem sets
II. Urine
d. Problem sets
2. Metabolite
I. Plasma
Introduction
c. Problem sets
II. Urine
d. Problem sets
I: Bioavailability, Bioequivalence, Drug product selection
1. Relative and Absolute Bioavailability
2. Factors Influencing Bioavailability
3. Methods of Assessing Bioavailability
I. in vivo
II. in vitro
III. Correlation
4. Bioequivalence
5. Bioavailability
6. Drug Product Selection
1.8.3 STUDY GROUP 3: APPLY THE TOOLS IN COMPROMISED PATIENTS.
J: Dosage regimen (Healthy, aged and diseased patients)
1. Multiple dose kinetics
2. Optimization of dosage regimen
3. Computer aided instruction
5. Computer aided consultation
6. Professional consultation process
End of Material for two credit course (six weeks semester - 2 weeks summer)
1.8.4 STUDY GROUP 4: APPLY THE TOOLS IN SPECIAL CASES.
K: Multicompartment Modeling
1. Parent compound plasma vs. time profile analysis
2. Multiple dose considerations
L: Protein Binding (healthy, aged and diseased patients)
1. Mass balance considerations / drug interactions
2. Effects of protein binding on pharmacokinetic parameters
Introduction
M: Non - linear (Michaelis - Menton) kinetics
End of material for three credit course (4 weeks semester, 2 weeks summer)
Introduction
1.9 Competency Statements Related To Pharmacokinetics
The profession of pharmacy has determined that there are minimum, entry level
abilities necessary for a pharmacist. These form the Standards of Practice for the
profession of pharmacy, as written by The National Association of Boards of Phar-
macy (who make the NAPLEX, coincidentally). It is important to note that these
abilities are not thought up by some faculty member who sits in his ivory tower
saying what he thinks is important. These are what pharmacists do. They have
been promulgated as competency statements They are also the basis for the state
board exams as well as the basis far your coursework while in the School of Phar-
macy. They are broken down into three general areas:
Area 1: Manage Drug Therapy to Optimize Patient Outcomes (Approximately
50% of Test)
Area 2: Assure the Safe and Accurate Preparation and Dispensing of Medications
(Approximately 25% of Test)
Area 3: Provide Drug Information and Promote Public Health (Approximately
25% of Test)
For a complete listing of competency statements please refer to the National Asso-
ciation of Boards of Pharmacys web site, www.nabp.net
1.9.1 SPECIFIC COMPETENCY STATEMENTS ADDRESSED IN THIS
COURSE
Area 1: Manage Drug Therapy to Optimize Patient Outcomes (Approxi-
mately 50% of Test)
1.1.0 Evaluate the patient and/or patient information to determine the presence of a
disease or medical condition, to determine the need for treatment and/or referral,
and to identify patient-specific factors that affect health, pharmacotherapy, and/or
disease management.
1.1.1 Identify and/or use instruments and techniques related to patient assessment
and diagnosis.
1.1.2 Identify and define the terminology, signs, and symptoms associated with
diseases and medical conditions.
Introduction
1.1.4 Identify patient factors, biosocial factors, and concurrent drug therapy that
are relevant to the maintenance of wellness and the prevention or treatment of a
disease or medical condition.
1.2.0 Assure the appropriateness of the patient's specific pharmacotherapeutic
agents, dosing regimens, dosage forms, routes of administration, and delivery sys-
tems.
1.2.1 Identify drug products by their generic, trade, and/or common names.
1.2.3 Evaluate drug therapy for the presence of pharmacotherapeutic duplications
and interactions.
1.2.5 Identify physicochemical properties of drug substances that affect their solu-
bility, pharmacokinetics, pharmacologic actions, and stability.
1.2.6 Interpret and apply pharmacokinetic principles to calculate and determine
appropriate drug dosing regimens.
1.2.7 Interpret and apply biopharmaceutic principles and the pharmaceutical char-
acteristics of drug dosage forms and delivery systems, to assure bioavailability and
enhance patient compliance.
1.3.0 Monitor the patient and/or patient information and manage the drug regimen
to promote health and assure safe and effective pharmacotherapy.
1.3.2 Evaluate patient information to determine the safety and effectiveness of
pharmacotherapy.
1.3.5 Identify and remedy interactions or contraindications with diagnostic or
monitoring tests or procedures.
Area 2: Assure the Safe and Accurate Preparation and Dispensing of Medica-
tions (Approximately 25% of Test)
2.1.0 Perform calculations required to compound, dispense, and administer medi-
cation.
2.1.1 Calculate the quantity of medication to be compounded or dispensed; reduce
and enlarge formulation quantities and calculate the quantity or ingredients needed
to compound the proper amount of the preparation.
2.1.3 Calculate the rate of drug administration.
Introduction
2.1.4 Calculate or convert drug concentrations, ratio strengths, and/or extent of
ionization.
2.2.0 Select and dispense medications.
2.2.3 Interpret and apply pharmacokinetic parameters and quality assurance data to
determine equivalence among manufactured drug products, and identify products
for which documented evidence of inequivalence exists.
2.2.5 Identify and describe the use of equipment and apparatus required to admin-
ister medications.
Area 3: Provide Drug Information and Promote Public Health (Approxi-
mately 25% of Test)
3.1.0 Access, evaluate, and apply information to promote optimal health care.
3.1.1 Identify the typical content and organization of specific sources of drug and
health information.
3.1.2 Interpret and evaluate data presented in textual, tabular, or graphic form.
3.1.3 Evaluate the suitability, accuracy, and reliability of information from refer-
ence sources by explaining and evaluating the adequacy of experimental design
and by applying and evaluating statistical tests and parameters.
Introduction
1.10 Pharmacokinetic Symbolism
Pharmacokinetics was developed in several locations simultaneously. Because of
this, the symbols used in the literature are not consistent. Provided each symbol is
rigorously defined prior to use, this inconsistency should not prove an insurmount-
able difficulty when assessing the literature. In this book, the symbolism below
will be generally used, though, as an illustration of the variety, some deviation may
be anticipated on occasions.
1.10.1 AMOUNT TERMS (UNIT: MASS)
amount remaining to be eliminated (excreted)
dose (or maintenance dose)
loading dose
amount of drug remaining to be absorbed at any time
amount of unchanged drug in body at any time
amount of metabolite in body at any time
cumulative amount of unchanged drug excreted into urine up to any time
cumulative amount of metabolite excreted into urine up to any time
maximum amount of unchanged drug in body
minimum amount of unchanged drug in body
average amount of unchanged drug in body (also Laplace transform)
minimum amount of unchanged drug in body necessary for pharmacologi-
cal response
ARE
D
D
L
X
a
X
X
m
X
u
X
mu
X
max
X
min
X
X
eff
Introduction
1.10.2 CONCENTRATION TERMS (UNITS MASS/VOLUME)
concentration of drug in blood at any time
concentration of drug in plasma at any time
Concentration of metabolite in plasma (or blood) at any time
average steady-state concentration of drug in plasma during a dosing
interval
maximum concentration of drug in plasma
minimum concentration of drug in plasma
average concentration of drug in plasma
dissociation constant of drug-protein complex
Michaelis-Menton rate constant
dissociation constant of drug-receptor complex
minimum effective concentration of drug or metabolite
minimum toxic concentration of drug or metabolite
1.10.3 VOLUME TERMS (UNIT: VOLUME)
apparent volume of unchanged drug distribution in compartment
apparent volume of metabolite distribution in compartment
physiological volume of plasma water
C
b
C
p
C
m
C
p
( )
ss
C
p
( )
max
C
p
( )
min
C
p
K
A
K
M
K
R
MEC
MTC
V
d
V
m
V
w
Introduction
1.10.4 TIME TERMS (UNIT: TIME)
time since administration of dose
duration of zero-order input
time since cessation of zero-order input
lag time
mean time during sampling interval
elimination half-life (biological half-life)
time for 50% removal
time when maximum amount or concentration occurs
duration of effective pharmacological response
dosing interval (greek theta)
time variable used in association with zero-order input
1.10.5 RATE CONSTANT TERMS (UNIT: RECIPROCAL TIME (*), MASS/TIME
(**)
apparent first-order rate constant for elimination, Summation of all
the ways the drug is eliminated (*)
apparent first-order rate constant for absorption (*)
apparent first-order rate constant for urinary (renal) excretion of unchanged
drug (*)
apparent first-order rate constant for metabolism of unchanged drug (*)
t
T
t'
t
0
t
t
t
0.5
t
max
t
dur
b
K k
e
K
d
K ,
i
, ,
k
a
k
u
k ,
r
k
m
Introduction
apparent first-order rate constant for excretion of metabolite (*)
apparent first-order transfer rate constant (*)
zero-order input rate constant (**)
zero-order infusion rate constant (**)
rate constant for decline in pharmacological effect (usual units:%/time)
hybrid first-order rate constant (*) (greek alpha)
hybrid first-order rate constant (*) (greek beta)
1.10.6 CLEARANCE TERMS (UNITS: VOLUME/TIME)
total body clearance (TBC)
renal clearance (RC)
metabolic clearance (MC)
creatinine clearance
hepatic clearance (HC)
1.10.7 RATE TERMS (UNITS: MASS/TIME (*), MASS/TIME, VOLUME (**),
VOLUME/TIME (***)
instantaneous rate of change of amount of unchanged drug (*)
measured rate of change of amount of unchanged drug (*)
rate of plasma flow through the liver (***)
k
mu
k
ij
k
0
Q
R
Cl
Cl
r
Cl
m
Cl
cr
Cl
H
dX
dt
-------
X
t
----
R
H
Introduction
rate of plasma flow through the kidney (***)
theoretical maximum rate of a process (**)
1.10.8 OTHER TERMS
area under the plasma concentration-time curve (units: time * mass/vol-
ume)
area under the first moment of the plasma concentration-time curve (units:
)
Mean Residence Time (units: )
Mean Absorption Time (units: )
Mean Dissolution Time (units: )
intensity of pharmacological effect
steady-state hepatic extraction ratio
steady-state renal extraction ratio
maximum intensity of pharmacological effect
fraction of administered dose ultimately absorbed
fraction remaining to be eliminated (excreted)
hematocrit (fractional volume of erythrocytes in whole blood)
number of elimination half-lives in a dosing interval
accumulation factor
intercept
R
r
V
M
AUC
AUMC
time
2
mass volume
MRT time
MAT time
MDT time
E
E
H
E
r
E
max
F
FRE
H
N
R
b
Introduction
fraction of drug that is free (unbound)
fraction of steady-state
slope (sometimes specifically for log dose-response plot)
number of doses
Laplace operator
indicates molar concentration
1.10.9 SUBSCRIPTS
at time zero
at time infinity
during steady-state
at time t
at time T
following dose n
difference between extrapolated and observed
intrinsic
index (i.e., 1,2,3)
index (i.e., 1,2,3)
1.10.10 SUPERSCRIPTS
extrapolated
f
f
ss
m
n
s
[ ]
0
ss
t
T
n
diff
int
i
j
x
Introduction
last measured value x
Introduction
1.11 First Lesson in Pharmacokinetics
It should be intuitively obvious to the most casual observer that the relative bioavailability of 2
simultaneous I.V. bolus doses of a drug is equal to the following: (EQ 1-1)
(EQ 1-2)
given that 100% bioavailability of a single I.V. bolus dose is equal to 1, and both
doses contain an equal mass of active drug.
For the struggling pharmacokinetics student, we would like to show the veracity of
this statement. Of course, it is obvious that; the reverse of the transpose is equal to
the transpose of the inverse in matrix theory. i.e.:
(EQ 1-3)
Also, it should be obvious that:
(EQ 1-4)
Consequently,
(EQ 1-5)
which means that:
(EQ 1-6)
By definition,
(EQ 1-7)
and
(EQ 1-8)
Thus:
x
1
[ ]
1
x
1
[ ]
1
( )!
1
--- +
,
_

lim

' ;

ln q sin ( )
2
q cos ( )
2
+ +
p 1 p tanh ( )
2
cosh
2
n
--------------------------------------------------
n 0 =
=
x
1
[ ]
1
x
1
[ ]
1
=
0! 1 =
x
1
[ ]
1
x
1
[ ]
1
( )! 1 =
1
1
--- +
,
_

lim

' ;

ln q sin ( )
2
q cos ( )
2
+ +
p 1 p tanh ( )
2
cosh
2
n
--------------------------------------------------
n 0 =
=
e 1
1
--- +
,
_
=
1 p 1 p tanh ( )
2
cosh =
Introduction
(EQ 1-9)
Also,
(EQ 1-10)
and
(EQ 1-11)
and
(EQ 1-12)
So, as we observed in equation 1,
(EQ 1-13)
under the stated conditions, two I.V. bolus doses given simultaneously will have
twice as much available drug as a single I.V. bolus dose.
You will agree, however, equation 1-1 is obvious and therefore is more easily
understood by a pharmacokineticist!
e ln q sin ( )
2
q cos ( )
2
+ +
1
2
n
-----
n 0 =
=
2
1
2
n
-----
n 0 =
=
1 e ln =
1 q sin ( )
2
q cos ( )
2
+ =
1 1 + 2 =
CHAPTER 2 Mathematics Review
Author: Michael Makoid, Phillip Vuchetich and John Cobby
BASIC MATHEMATICAL SKILLS OBJECTIVES
1. Given a data set containing a pair of variables, the student will properly construct
(III) various graphs of the data.
2. Given various graphical representations of data, the student will calculate (III) the
slope and intercept by hand as well as using linear regression.
3. The student shall be able to interpret (V) the meaning of the slope and intercept
for the various types of data sets.
4. The student shall demonstrate (III) the proper procedures of mathematical and
algebraic manipulations.
5. The student shall demonstrate (III) the proper calculus procedures of integration
and differentiation.
6. The student shall demonstrate (III) the proper use of computers in graphical simu-
lations and problem solving.
7. Given information regarding the drug and the pharmacokinetic assumptions for
the model, the student will construct (III) models and develop (V) equations of the
ADME processes using LaPlace Transforms.
8. The student will interpret (IV) a given model mathematically.
9. The student will predict (IV) changes in the final result based on changes in vari-
ables throughout the model.
10. The student will correlate (V) the graphs of the data with the equations and mod-
els so generated.
Mathematics Review
2.1 Concepts of Mathematics
Pharmacokinetcs is a challenging field involving the application of mathematical
concepts to real situations involving the absorbtion, distribution, metabolism and
excretion of drugs in the body. In order to be successful with pharmacokinetics, a
certain amount of mathematical knowledge is essential.
This is just a review.
Look it over. You should
be able to do all of these
manipulations.
This chapter is meant to review the concepts in mathematics essential for under-
standing kinetics. These concepts are generally taught in other mathematical
courses from algebra through calculus. For this reason, this chapter is presented as
a review rather than new material. For a more thorough discussion of any particu-
lar concept, refer to a college algebra or calculus text.
Included in this section are discussions of algebraic concepts, integration/differen-
tiation, graphical analysis, linear regression, non-linear regression and the LaPlace
transform. The Scientist and PKAnalyst are the computer programs used in this
course.
Something new -
LaPlace transforms.
Useful tool.
A critical concept introduced in this chapter is the LaPlace transform. The LaPlace
transform is used to quickly solve (integrate) ordinary, linear differential equa-
tions. The Scientist by Micromath Scientific Software, Inc.
1
is available for work-
ing with the LaPlace transform for problems throughout the book.
1. MicroMath Scientific Software, Inc., P.O. Box 21550, Salt Lake City, UT 84121-0550,
http://www.micromath.com
Mathematics Review
2.2 Mathematical Preparation
2.2.1 ZERO AND INFINITY
Any number multiplied by zero equals zero. Any number multiplied by infinity
equals infinity. Any number divided by zero is mathematically undefined.
Any number divided by infinity is mathematically undefined.
2.2.2 EXPRESSING LARGE AND SMALL NUMBERS
Large or small numbers can be expressed in a more compact way using indices.
How Does Scientific
Notation Work?
Examples: 316000 becomes
0.00708 becomes
In general a number takes the form:
Where A is a value between 1 and 10, and n is a positive or negative integer
The value of the integer n is the number of places that the decimal point must be
moved to place it immediately to the right of the first non-zero digit. If the decimal
point has to be moved to its left then n is a positive integer; if to its right, n is a
negative integer.
Because this notation (sometimes referred to as Scientific Notation) uses indi-
ces, mathematical operations performed on numbers expressed in this way are sub-
ject to all the rules of indices; for these rules see Section 2.2.4.
A shorthand notation (AEn) may be used, especially in scientific papers. This may
be interpreted as , as in the following example:
2.28E4 =
( )
3.16 10
5
7.08
3
10
A 10
n
A 10
n
2.28
4
10 22800 =
Mathematics Review
2.2.3 SIGNIFICANT FIGURES
A significant figure is any digit used to represent a magnitude or quantity in the
place in which it stands. The digit may be zero (0) or any digit between 1 and 9.
For example:
How do I determine the
number of significant
figures?
Examples (c) to (e) illustrate the exceptions to the above general rule. The value 10
raised to any power, as in example (c), does not contain any significant figures;
hence in the example the four significant figures arise only from the 10.65. If one
or more zeros immediately follow a decimal point, as in example (e), these zeros
simply serve to locate the decimal point and are therefore not significant figures.
The use of a single zero preceding the decimal point, as in examples (d) and (e), is
a commendable practice which also serves to locate the decimal point; this zero is
therefore not a significant figure.
What do significant fig-
ures mean?
Significant figures are used to indicate the precision of a value. For instance, a
value recorded to three significant figures (e.g., 0.0602) implies that one can reli-
ably predict the value to 1 part in 999. This means that values of 0.0601, 0.0602,
and 0.0603 are measurably different. If these three values cannot be distinguished,
they should all be recorded to only two significant figures (0.060), a precision of 1
part in 99.
After performing calculations, always round off your result to the number of sig-
nificant figures that fairly represent its precision. Stating the result to more signifi-
cant figures than you can justify is misleading, at the very least!
2.2.4 RULES OF INDICES
What is an index? An index is the power to which a number is raised.
Example: where A is a number, which may be positive or negative, and n is
the index, which may be positive or negative.
TABLE 2-1. Significant Figures
Value
Significant
Figures
Number of
Significant
Figures
(a) 572 2,5,7 3
(b) 37.10 0,1,3,7 4
(c)
10.65 x 10
4
0,1,6,5 4
(d) 0.693 3,6,9 3
(e) 0.0025 2,5 2
A
n
Mathematics Review
Sometimes n is referred to as the exponent, giving rise to the general term, Rules
of Exponents. There are three general rules which apply when indices are used.
(a) Multiplication

(b) Division
(c) Raising to a Power
There are three noteworthy relationships involving indices:
(i) Negative Index
As n tends to infinity then .
(ii) Fractional Index
(iii) Zero Index
A
n
A
m
A =
n m +
A
n
B
m
A
B
---
,
_
n
B
n m +
=
A
n
A
m
------- A
n m
=
A
n
B
m
-------
A
B
---
,
_
n
B
n m
=
A
n
( )
m
A
nm
=
A
n 1
A
n
------ = n ( ) A
n
0
A
1
n
---
A
n
=
A
0
1 =
Mathematics Review
2.2.5 LOGARITHMS
What is a logarithm? Some bodily processes, such as the glomerular filtration of drugs by the kidney,
are logarithmic in nature. Logarithms are simply a way of succinctly expressing a
number in scientific notation.
In general terms, if a number (A) is given by
then
where log signifies a logarithm to the base 10, and is the value of the logarithm
of (A).
Example: 713000 becomes ,
and , thus 713000 becomes
and
Logarithms to the base 10 are known as Common Logarithms. The transformation
of a number (A) to its logarithm (n) is usually made from tables, or on a scientific
calculator; the reverse transformation of a logarithm to a number is made using
anti-logarithmic tables, or on a calculator.
What is the characteris-
tic? the mantissa?
The number before the decimal point is called the characteristic and tells the place-
ment of the decimal point (to the right if positive and to the left if negative). The
number after the decimal is the mantissa and is the logarithm of the string of num-
bers discounting the decimal place.
2.2.6 NATURAL LOGARITHMS
What is a natural loga-
rithm?
Instead of using 10 as a basis for logarithms, a natural base (e) is used. This natural
base is a fundamental property of any process, such as the glomerular filtration of a
drug, which proceeds at a rate controlled by the quantity of material yet to undergo
the process, such as drug in the blood. To eight significant figures, the value of the
transcendental function, e, is
....
A 10
n
=
A ( ) log n =
n
7.13 10
5
7.13 10
0.85
= 10
0.85
10
5
10
5 0.85 + ( )
10
5.85
= =
713000 ( ) log 5.85 =
e 2.7182818 =
Mathematics Review
Strictly speaking,
Where is an integer ranging from 1 to infinity ,
denotes the summation from , and
! is the factorial (e.g., 6! = 6x5x4x3x2x1= 720)
In general terms, if a number (A) is given by , then by definition,
Where, ln signifies the natural logarithm to the base , and is the value of the
natural logarithm of .
Natural logarithms are sometimes known as Hyperbolic or Naperian Logarithms;
again tables are available and scientific calculators can do this automatically. The
anti-logarithm of a natural logarithm may be found from exponential tables, which
give the value of for various values of n.
How are natural loga-
rithms and common
logarithms related?
Common and natural logarithms are related as follows:
, and
Because logarithms are, in reality, indices of either 10 or , their use and manipu-
lation follow the rules of indices (See Section 2.2.4).
(a) Multiplication:
To multiply , where and ; .
By definition,
e 1
1
x!
----
x 1 =
+ =
x ( )
x 1 =
x 1 to x = =
A e
n
=
A ( ) ln n =
e n
A
e
n
x ln
x log
A ( ) ln 2.303 A ( ) log =
A ( ) log 0.4343 A ( ) ln =
e
N M N e
n
= M e
m
= NM e
n
e
m
e
n m +
= =
Mathematics Review
;
but
and
,
hence
Thus, to multiply two numbers (N and M) we take the natural logarithms of each,
add them together, and then take the anti-logarithm (the exponent, in this case) of
the sum.
(b) Division
(c) Number Raised to a Power
There are three noteworthy relationships involving logarithms:
(i) Number Raised to a Negative Power
As tends to infinity , then
(ii) Number Raised to a Fractional Power
NM ( ) ln n m + =
n N ( ) ln =
m M ( ) ln =
NM ( ) ln N ( ) ln M ( ) ln + =
N
M
-----
,
_
ln N ( ) ln M ( ) ln =
N
m
( ) ln m N ( ) ln =
N
m
( ) ln m N ( ) ln m
1
N
----
,
_
ln = =
m m ( ) N
m
( ) ln
Mathematics Review
(iii) Logarithm of Unity
2.2.7 NEGATIVE LOGARITHMS
The number 0.00713 may be expressed as:
, or
, or
.
Hence, , which is the result generated by most calculators.
However, another representation of a negative logarithm (generally used by refer-
encing a log table):
log (0.00713) = 3.85
The 3 prior to the decimal point is known as the characteristic of the logarithm; it
can be negative (as in this case) or positive, but is never found in logarithmic
tables. The .85 following the decimal point is known as the mantissa of the loga-
rithm; it is always positive, and is found in logarithmic tables.
In fact 3 is a symbolic way of writing minus 3 (-3) for the characteristic. In every
case the algebraic sum of the characteristic and the mantissa gives the correct
value for the logarithm.
Example: log (0.00713) = 3.85
Add -3 and 0.85
Result is -2.15, which is the value of
N
m
( ) ln N
1
m
----
,

_
ln
1
m
---- N ( ) ln = =
1 ( ) ln 1 ( ) log 0 = =
7.13
3
10
10
0.85
10
3
10
2.15
0.00713 ( ) log 2.15 =
0.00713 ( ) log
Mathematics Review
The reason for this symbolism is that only positive mantissa can be read from anti-
logarithmic tables, and hence a positive mantissa must be the end result of any log-
arithmic manipulations. Note that while there are negative logarithms (when N <
1), they do not indicate that number itself is negative; the sign of a number (e.g., -
N) is determined only by inspection following the taking of anti-logarithms.
2.2.8 USING LOGARITHMIC AND ANTI-LOGARITHMIC TABLES
Though the preferred method to using logarithms is with a calculator or computer,
the understanding of how the number is being manipulated may be important in
understanding the use of logarithms. (See the end of this chapter for Logarithm
tables).
(a) Find the log of (62.54)
Look up the mantissa for 6254 in a table of logarithms: it is 7962.
Hence, and
(b) Find the log of (0.00329)
The mantissa for 329 is 5172 Hence, log(0.00329) = 3.5172.
Note that in both examples the value of the characteristic is the integer power to
which 10 is raised when the number is written in scientific notation.
How do I multiply using
logarithms?
(c) Multiply 62.54 by 0.00329
log (62.54) = 1.7972
log (0.00329) = 3.5172
log (62.54 + log (0.00329) = 1.7962+3.5172 = 1.7962-3+ 0.5172=-0.6866
0.6866=1.3134
62.54 6.254
1
10 =
6.254
1
10 10
0.7962
10
1
10
1.7962
= = 62.54 ( ) log 1.7962 =
0.00329 3.29
3
10 =
Mathematics Review
(d) We wish to find anti-log (1.3134) Look up the anti-log for the 0.3134 (man-
tissa) in a table: it is 2058.
Antilog (1.3134) =
Hence, antilog (1.3134) = 0.2058
How do I divide using
logarithms?
log (62.54) - log (0.00329) = 1.796 - 3.5172=1.796 +3 - 0.5172=4.2788
antilog 4.2788 = 19002
2.2.9 DIMENSIONS
What is a unit? There are three fundamental dimensions which are used in various combinations to
express the properties of matter. Each of these dimensions has been assigned a def-
inite basic unit, which acts as a reference standard.
How are units made big-
ger and smaller?
In the metric system, which emerged from the French Revolution around 1799,
there are various prefixes which precede the basic units and any derived units. The
prefixes indicate the factor by which the unit is multiplied. When the index of the
factor is positive the prefixes are Greek and have hard, consonant sounds. In con-
trast, when the index is negative, the prefixes are Latin and have soft, liquid
sounds. (see Table 2-3).
How big is big? Examples: An average adult male patient is assumed to have a mass of 70 kilo-
grams (70 kg). An average adult male patient is assumed to have a height of 180
centimeters (180 cm). A newly minted nickel has a mass of 5.000 g. Doses of
drugs are in the mg (10
-3
g) range (occasionally g) never Kg (10
3
g) or larger. Stu-
dents have told me that the dose that they have calculated for their patient is 10
8
g
(converting to common system - ~ 100 tons). I doubt it. Get familiar with this sys-
tem. Note that the plural of Kg or cm is Kg or cm; do not add an s. In pharmacy
there are two derived units which are commonly used, even though they are
related to basic units. The Liter (L) is the volume measurement and is a cube 10
cm on a side (1L = (10cm)
3
= 1000 cm
3
) while the concentration measurement
and has the units of Mass per Volume.
2.058
1
10
TABLE 2-2 Dimensions
Dimension
Dimensional
Symbol Unit Unit Symbol
Length L meter m
Mass M gram g
Time T second sec
Mathematics Review
Why should I use units? Whenever the magnitude of a measured property is stated, it is imperative to state
the units of the measurement. Numbers are useless by themselves.
Example: The procainamide concentration range is 4-8 g/ml; stating the range
without units may lead to a potentially lethal error in which procainamide is
administered in a sufficient dose to attain a range of 4-8 mg/ml, which is 1000
times too large and would give rise to cardiac arrest.
2.2.10 DIMENSIONAL ANALYSIS
How are units useful? It is a general rule that the net dimensions (and units) on the two sides of any equa-
tion should be equal. If this is not so, the equation is necessarily meaningless.
Consider the following equation which defines the average concentration of a drug
in blood after many repeated doses,
TABLE 2-3 Scale of Metric system and SI
Name Symbol Multiplication Factor Name Symbol Multiplication Factor
exa- E deci- d
peta- P centi- c
tera- T milli- m
giga- G micro-
mega- M nano- n
kilo- k pico- p
hecto- h femto- f
deca- da atto- a
TABLE 2-4
Dimension
Dimensional
Symbol Unit
Unit
Symbol
Volume V liter l
Concentration C grams/liter g/l
10
18
10
1
10
15
10
2
10
12
10
3
10
9

10
6
10
6
10
9
10
3
10
12
10
2
10
15
10
1
10
18
C
b
( )
FD
VK
----------- =
Mathematics Review
Where:
is the fraction of the administered dose ultimately absorbed (Dimensions: none),
is the mass of the repeated dose (Dimension: M),
is the apparent volume of distribution of the drug (Dimension: )
is the apparent first-order rate constant for drug elimination (Dimension: ),
and is the dosing interval (Dimension: )
Writing the dimensions relating to the properties of the right-hand side of the equa-
tion gives:
Thus has the dimensions of , which are correctly those of concentration.
Sometimes dimensional analysis can assist an investigator in proposing equations
which relate several properties one with the other. If the units cancel, and you end
up with the correct unit of measure, you probably did it right. If you obtain units
that do not make sense, its guaranteed sure that you did it wrong.
F
D
V V L =
K T
1
T
M
V T
1
T
------------------------
M
V
----- =
C
b
( )
M
V
-----
Mathematics Review
2.3 Calculus
What is Calculus? Calculus concerns either the rate of change of one property with another (differen-
tial calculus), such as the rate of change of drug concentrations in the blood with
time since administration, or the summation of infinitesimally small changes (inte-
gral calculus), such as the summation of changing drug concentrations to yield an
assessment of bioavailability. In this discussion a few general concepts will be pro-
vided, and it is suggested an understanding of graphical methods should precede
this discussion.
2.3.1 DIFFERENTIAL CALCULUS
2.3.2 NON-LINEAR GRAPHS
Consider the following relationship:
As can be seen from the graph (Figure 2-1), a non-linear plot is produced, as
expected.
FIGURE 0-1. y=x
3
(Question: How could the above data be modified to give a linear graph?)
TABLE 2-5 x, y sample data
x 0 1 2 3 4
y 0 1 8 27 64
y x
3
=
0
10
20
30
40
50
60
70
1 2 3 4
Mathematics Review
2.3.3 SLOPE OF NON-LINEAR GRAPH
As with a linear graph,
Where is the incremental change in y and is the incremental change in x
But, as can be seen (Figure 1), the slope is not constant over the range of the graph;
it increases as x increases. The slope is a measure of the change in y for a given
change in x. It may then be stated that:
the rate of change of y with respect to x varies with the value of x.
2.3.4 VALUE OF THE SLOPE
We need to find the value of the slope of the line when (See Figure
1). Hence, we may choose incremental changes in x which are located around
.
As may be seen, the value of the slope tends towards a value of 12.000 as the
magnitude of the incremental change in x becomes smaller around the chosen
value of 2.0. Were the chosen incremental changes in x infinitesimally small, the
true value of the slope (i.e., 12.000) would have appeared in the final column of
the above table.
y
2
y
1
x
2
x
1
----------------
y
x
------ =
y x
FIGURE 0-2. / when
0 4 4 0 64 64 16.000
1 3 2 1 27 26 13.000
1.5 2.5 1.0 3.375 15.625 12.250 12.250
1.8 2.2 0.4 5.832 10.648 4.816 12.040
1.9 2.1 0.2 6.859 9.261 2.042 12.010
1.95 2.05 0.1 7.415 8.615 1.200 12.003
y x
3
= x 2 =
x 2
y x x 2
x
1
x
2 x
y
1
y
2 y
y
x
------
y
x
------
,
_
Mathematics Review
Calculus deals with infinitesimally small changes. When the value of is infini-
tesimally small it is written dx and is known as the derivative of x. Hence,
Where dy/dx is the derivative of y with respect to x and indicates some func-
tion of x.
2.3.5 DIFFERENTIATION FROM FIRST PRINCIPLES
Differentiation is the process whereby the derivative of y with respect to x is
found. Thus the value of dy/dx, in this case, is calculated.
(a) Considering again the original expression:
(b) Let the value of y increase to because x increases to .
Hence,
(EQ 1-14)
Multiplying out:
(EQ 1-15)
(c) The change in y is obtained by subtraction of the original expression from the
last expression. (i.e., Eq. 2 - Eq. 1)
(EQ 1-16)
Dividing throughout to obtain the derivative,
When dx is infinitesimally small, its magnitude tends to zero . The limit-
ing value of this tendency must be . At this limit,
x
dy
dx
------ f x ( ) =
f x ( )
y x
3
=
y dy + x dx +
y dy + x dx + ( )
3
=
y dy + x
3
3x
2
dx ( ) 3x dx ( )
2
dx ( )
3
+ + + =
dy 3x
2
dx ( ) 3x dx ( )
2
dx ( )
3
+ + =
dy
dx
------ 3x
2
3x dx ( ) dx ( )
2
+ + =
dx 0 ( )
dx 0 =
Mathematics Review
(EQ 1-17)
Hence the derivative of y with respect to x at any value of x is given by .
(d) In section 2.3.4 we saw how the true value of the slope (i.e., dy/dx) would be
12.0 when . This is confirmed by substituting in Equation 1-16.
2.3.6 RULE OF DIFFERENTIATION
Although the rate of change of one value with respect to another may be calculated
as above, there is a general rule for obtaining a derivative.
Let x be the independent variable value, y be the dependent variable value, A be a
constant, and n be an exponential power.
The general rule is:
If
then
The Rules of Indices may need to be used to obtain expressions in the form
(e.g., if )
2.3.7 THREE OTHER DERIVATIVES
(a) If ,
then (i.e., is constant)
dy
dx
------ 3x
2
=
3x
2
x 2 =
dy
dx
------ 3x
2
3 2
2
( ) 12 = = =
y Ax
n
=
dy
dx
------ nAx
n 1
=
y Ax
n
=
y x
5
=
y Ax
0
=
y A = y
Mathematics Review
Hence,
Thus the derivative of a constant is always zero.
(b) Accept that if
then .
This derivative is important when considering apparent first-order processes, of
which many bodily processes (e.g., excretion of drugs) are examples.
(c) Accept that if where B and A are constants, and e is the natural
base then
This derivative will be useful in pharmacokinetics for finding the maximum and
minimum concentrations of drug in the blood following oral dosing.
2.3.8 A SEEMING ANOMALY
Consider the following two expressions:
(a) If , then
(b) If ,
then
Both of the original expressions, although different, have the same derivative. This
fact is recognized later when dealing with integral calculus.
dy
dx
------ 0 =
y x ( ) ln =
dy
dx
------
1
x
--- =
y Be
Ax
=
dy
dx
------ ABe
Ax
=
y Ax
n
=
dy
dx
------ nAx
n 1
=
y Ax
n
A + =
dy
dx
------ nAx
n 1
0 + nAx
n 1
= =
Mathematics Review
2.3.9 INTEGRAL CALCULUS
Generally integral calculus is the reverse of differential calculus. As such it is used
to sum all the infinitesimally small units (dy) into the whole value (y).
Thus,
, where the symbol for integration.
2.3.10 RULE OF INTEGRATION
The derivative expression may be written:
, or
To integrate,
A general rule states:
Where A is the constant of integration However, there is one exception - the rule
is not applicable if
Example: If (See section 2.3.5),
then , and
y d
y = is
dy
dx
------ Ax
n
=
dy Ax
n
dx =
y y d
Ax
n
x d
A x
n
x d
= = =
A x
n
x d
Ax
n 1 +
n 1 +
---------------- A + =
n 1 =
dy
dx
------ 3x
2
=
y
3x
2 1 +
2 1 +
--------------- A + =
y x
3
A + =
Mathematics Review
2.3.11 THE CONSTANT OF INTEGRATION
There has to be a constant in the final integrated expression because of the seeming
anomaly referred to in section 2.3.8. As mentioned, both and
will give, on differentiation, .
So whether or not a constant is present and, if so, what is its value, can only be
decided by other knowledge of the expression. Normally this other knowledge
takes the form of knowing the value of y when .
In the case of our graphical example we know that when , then . The
integrated expression for this particular case is:
, therefore
, thus
In some examples, such as first-order reaction rate kinetics, the value of A is not
zero.
2.3.12 THE EXCEPTION TO THE RULE
It occurs when
Upon integration,
This is the reverse of the derivative stated in section 2.3.10 (b).
2.3.13 A USEFUL INTEGRAL
Accept that if,
y x
3
= y x
3
A + =
dy
dx
------ 3x
2
=
x 0 =
x 0 = y 0 =
y x
3
A + =
0 0
3
A + = A 0 =
n 1 =
y A x
1
x d
A
1
x
--- x d
= =
y A x ( ) ln A + =
dy
dx
------ Be
Ax
=
Mathematics Review
then,
This integral will be useful for equations which define the bioavailability of a drug
product.
2.3.14 EXAMPLE CALCULATIONS
(a) Consider,
Where is the drug concentration in a dissolution fluid at time .
Then, multiplying out,
The rate of dissolution at time t is
So at any time, the rate may be calculated.
(b) Consider,
Then rearranging,
The integral of is:
y
Be
Ax
A
----------- A + =
c 3t
2
t 2 ( ) 5 + =
c t
c 3t
3
6t
2
5 + =
dc
dt
------ 9t
2
12t =
dc
dt
------ 3t t 4 ( ) 9t
2
12t = =
dc 9t
2
dt 12t dt =
c
c c d
3t
3
A 6t
2
B + + = =
Mathematics Review
where is a second constant.
Adding the two constants together,
where
We know, from previous work, that when , then
Substituting , the final expression becomes:
Which is the initial expression in example (a) above.
(c) Following administration of a drug as an intravenous injection,
Where is the plasma concentration of a drug at time
is the apparent first-order rate constant of elimination.
Rearranging,
This integral is the exception to the rule (see section 2.3.12).
We know that when , .
B
c 3t
3
6t
2
D + = =
D A B + =
t 0 = c 5 =
5 D =
c 3t
2
6t
2
5 + + =
dC
p
dt
------------- KC
p
=
C
p
t
K
K dt
1
C
p
------ dC
p
=
Kt K t d
1
C
p
------
C
p
d = =
Kt C
p
( ) ln A + =
t 0 = C
p
C
p
( )
0
=
Mathematics Review
Substituting,
Or,
Hence
or,
or,
0 C
p
( )
0
ln A + =
A C
p
( )
0
ln =
Kt C
p
( ) ln C
p
( )
0
ln =
C
p
( ) ln C
p
( )
0
ln Kt =
C
p
C
p
( )
0
e
Kt
=
Mathematics Review
2.4 Graphs
Why do we graph? We would like to agonize the chaotic world around us so that we can predict (see
into the future) and retrodict (see into the past) what will happen or has happened.
Our recorded observations are collectively known as data. We make a theory
about what we think is happening and that theory is expressed in an equation. That
determines our paradigm of how we see the world. This paradigm is expressed as
a graph. The language of science is mathematics and graphs are its pictures.
What is a graph? A graph is simply a visual representation showing how one variable changes with
alteration of another variable. The simplest way to represent this relationship
between variables is to draw a picture. This pictorializing also is the simplest way
for the human mind to correlate, remember, interpolate and extrapolate perfect
data. An additional advantage is it enables the experimenter to average out small
deviations in experimental results (non-perfect, real data) from perfect data. For
example:
TABLE 2-6
English Science
Observations Data
Theory Equations
Paradigms (pictures) Graphs
TABLE 2-7 Perfect vs. Real data
Perfect Real
-3 -5 -4.6
-2 -3 -3.4
-1 -1 -0.6
0 +1 +0.8
+1 +3 +3.4
+2 +5 +4.4
Mathematics Review
FIGURE 0-3. Plot of Perfect vs. Real data
Simply looking at the columns x and y (real) it might be difficult to see the rela-
tionship between the two variables. But looking at the graph, the relationship
becomes apparent. Thus, the graph is a great aid to clear thinking. For every graph
relating variables, there is an equation and, conversely for every equation there is a
graph. The plotting of graphs is comparatively simple. The reverse process of find-
ing an equation to fit a graph drawn from experimental data is more difficult,
except in the case of straight lines.
2.4.1 GRAPHICAL CONVENTIONS
How are graphs made? Certain conventions have been adopted to make the process of rendering a data set
to a graphical representation extremely simple.
The y variable, known as the dependent variable, is depicted on the vertical axis
(ordinate); and the x variable, known as the independent variable, is depicted on
the horizontal axis (abscissa). It is said that y varies with respect to x and not
x varies with y.
A decision as to which of the two related variables is dependent can only be made
be considering the nature of the experiment. To illustrate, the plasma concentration
of a drug given by IV bolus depends on time. Time does not depend on the plasma
concentration. Consequently, plasma concentration would be depicted on the y
axis and time on the x axis.

x
y
-3 -2 -1 0 1 2
-6
-4
-2
0
2
4
6
Mathematics Review
Any point in the defined space of the graph has a unique set of coordinates: 1) the
x value which is the distance along the x axis out from the y axis and always
comes first; and 2) the y value which is the distance, along the y axis up or
down from the x axis, and always comes second. Several points are shown in
Figure 2. For example, (0,1) is on the line and (1,0) is not.
The intersection of x and y axis is the origin with the coordinates of (0,0). In two
dimensional spaces, the graph is divided into 4 quadrants from (0,0), numbered
with Roman numerals from I through IV. It should be readily apparent that the
coordinates for all points within a particular quadrant are of the same sign type i.e.,
A line (or curve) on a graph is made up of an infinite number of points, each of
which has coordinates that satisfy a given equation. For example, each point on the
line in Figure 2 is such at its coordinates fit the equation . That is for
any value of x (the independent variable), multiplying the x value by 2 and adding
1 results in the y value (the dependent variable).
2.4.2 STRAIGHT LINE GRAPHS
What is a straight line? A graph is a straight line (linear) only if the equation from which it is derived has
the form
Where:
y = dependent variable
x = independent variable
m = slope of the straight line =
b = the y intercept (when x = 0)
or if the equation can be linearized, e.g.,
is not linear
TABLE 2-8 Quadrants on a cartesian graph
Quadrant II (-x, +y) Quadrant I (+x, +y)
Quadrant III (-x, -y) Quadrant IV (+x, -y)
y 2x 1 + =
y mx b + =
y
x
------
y be
mx
=
Mathematics Review
However.
is of the same general form as:
and consequently a plot of (the dependent variable) versus (the indepen-
dent variable) will yield a straight line with a slope of and an intercept of .
Expressions of any other form are non linear. For example:
An expression relating the plasma concentration of a drug over time .
this relationship put in linear perspective yields:
, which is in the form
The graphs that yield a straight line are the ones with the ordinate being ,
and the abscissa being .
Any other combination of functions of and will be non-linear, e.g.,
versus
versus
versus
The appropriate use of a natural logarithm in this case serves to produce linearity.
However, the use of logarithms does not automatically straighten a curved line in
all examples. Some relationships between two variables can never be resolved into
a single straight line, e.g.,
y ln b ln mx + =
y b mx + =
y ln x
m b ln
C
p
( ) t ( )
C
p
C
p0
e
Kt
=
C
p
ln C
p0
ln Kt =
y b mx + =
C
p0
ln
t
C
p
t
C
p
t
C
p
t ln
C
p
ln t ln
y k
0
k
1
x
n m ( )
k
2
x
n m 1 + ( )
k
n
( )x
x
+ + + + =
Mathematics Review
where
or

(It is possible to resolve this equation into the summation of two linear graphs
which will be shown subsequently.)
2.4.3 THE SLOPE OF A LINEAR GRAPH (M)
What is the slope of a
straight line?
From the equation a prediction may be made as to whether the slope is positive or
negative. In the previous example, the slope is negative, i.e:
The differences in both the y-values and the x-values may be measured graphically
to obtain the value of the slope, m. Then knowing the value of m, the value of
may be found.
n 2 n ; m 1 + =
C
p
K
a
FD
V K
a
K ( )
------------------------- e
Kt
e
K
a
t
( ) =
TABLE 2-9 Sample data of caffeine elimination
(min)
12 3.75 1.322
40 2.80 1.030
65 2.12 0.751
90 1.55 0.438
125 1.23 0.207
173 0.72 -0.329
m K =
t
C
p
g
mL
--------
,
_
C
p
ln
K
Mathematics Review
FIGURE 0-4. Plasma Concentration of caffeine over time
2.4.4 LINEAR REGRESSION: OBTAINING THE SLOPE OF THE LINE
The equation for a straight line is:
Where y is the dependent variable
x is the independent variable
m is the slope of the line
b is the intercept of the line
The equation for the slope of the line using linear regression is:
And the intercept is
C
p
( )

0 50 100 150 200
Time (min)
10
-1
10
0
10
1
C
a
f
f
e
i
n
e

C
o
n
c
e
n
t
r
a
t
i
o
n

(
u
g
/
m
L
)

y m x b + =
m
x ( ) y ( ) ( ) n x y ( ) ( )
x ( ) [ ]
2
n x
2
( ) ( )
--------------------------------------------------------------------- =
b y m x ( ) =
Mathematics Review
Using the data from table 2-10 in the equation for the slope of the line

and the intercept would be . Note that this is
. In oder to find the , the anti-ln of must be taken. i.e.
It is important to realize that you may not simply take any two data pairs in the
data set to get the slope. In the above data, if we simply took two successive data
pairs from the six data pairs in the set, this would result in five different slopes
ranging from -0.0066 to -0.0125 as shown in table 2-11. Clearly, this is
unacceptable. Even to guess, you must plot the data, eyeball the best fit line by
placing your clear straight edge through the points so that it is as close to the data
as possible and look to make sure that there are an equal number of points above
the line as below. Then take the data pairs from the line, not the data set.
TABLE 2-10 Linear Regression for data in table 2-9
12 1.322 144 15.864
40 1.030 1600 41.2
65 0.751 4225 48.815
90 0.438 8100 39.42
125 0.207 15625 25.875
173 -0.329 29929 -56.917
X Y X
2
X Y
X 505 = Y 3.239 =
X
2
59623 =
XY 114.257 =
X ( )
2
255025 =
x
x
n
------ 4.167 = = y
y
n
------ 0.5398 = =
m
505 3.239 ( ) 6 114.257 ( )
255025 6 59623 ( )
--------------------------------------------------------------------- 0.01014
= =
b 0.5398 0.01014 4.167 ( ) 1.4229 = =
C ln C
p0
b
Cpo e
b
e
1.4229
4.15 = = =
x y ( )
Mathematics Review
2.4.5 PARALLEL LINES
Two straight lines are parallel if they have the same slope.
Calculating for the intercept of a linear graph (b):
(a) Not knowing the value of m;
The graph may be extrapolated, or calculations performed, at the situation where
. In this case .
(b) Knowing the value of m;
There are two ways: for any point on the graph:
Hence, b may be calculated from a knowledge of and . Secondly, the graph
may be extrapolated or calculations performed, at the situation where . In
this case,
TABLE 2-11 Sample slope data from figure 0-4
Time (x) ln Conc. (y)
12 1.322 -28 0.292 -0.0104
40 1.030 -25 0.28 -0.0112
65 0.751 -25 0.312 -0.0125
90 0.438 -35 0.231 -0.0066
125 0.207 -48 0.536 -0.0112
173 -0.329
x y
y
x
------
t 0 = b C
p0
ln =
y
1
mx
1
b + =
b y
1
mx
1
=
y
1
x
1
t 0 =
b C
p
ln =
Mathematics Review
2.4.6 GRAPHICAL EXTRAPOLATIONS
How far can I predict? It is dangerous to extrapolate on non-linear graphs, and it is unwise to extrapolate
too far on linear graphs. Most often extrapolation is used to find the value of y at a
selected value of x.
If the size of the graph does not permit physical extrapolation to the desired value,
the required result may be obtained by calculation. The values of m and b must be
found as shown above. Then:
,
where is the selected value of x, and
is the new calculated value for y.
2.4.7 SIGNIFICANCE OF THE STRAIGHT LINE
The more closely the experimental points fit the best line, and the higher the num-
ber of points, the more significant is the relationship between y and x. As you may
expect, statistical parameters may be calculated to indicate the significance.
What good is a straight
line?
By using all the experimental data points, calculations may be made to find the
optimum values of the slope m, and the intercept, b. From these values the corre-
lation coefficient (r).and the t-value may be obtained to indicate the significance.
Exact details of the theory are available in any statistical book, and the calculations
may most easily be performed by a computer using The Scientist or PKAnalyst in
this course.
The advantage of computer calculation is that it gives the one and only best fit to
the points, and eliminates subjective fitting of a line to the data.
2.4.8 GRAPHICAL HONESTY
How many points are
needed?
Any graph drawn from 2 points is scientifically invalid. Preferably, straight-line
graphs should have at least 3 - 5 points, and non-linear graphs a few points more.
Can I discard points that
dont fit?
As a graph is a visual representation which enables the experimenter to average
out the small deviations in results from the perfect result, no one result can be
unjustifiably ignored when the best fitting line is drawn. Still, an errant point
may be justifiably ignored if there were unusual experimental circumstances
which may have caused the deviation. Thus it is not justifiable to omit a point
solely because it does not fit.
y' mx' b + =
x'
y'
Mathematics Review
2.4.9 AXES WITH UNEQUAL SCALES
In mathematical studies, the scales of the x and y are almost always equal but very
often in plotting chemical relations the two factors are so very different in magni-
tude that this can not be done. Consequently, it must be borne in mind that the rela-
tionship between the variables is given by the scales assigned to the abscissa and
ordinate rather than the number of squares counted out from the origin.
FIGURE 0-5.
For example (shown in Figure 0-5), these two parabolic curves represent the same
equation the only difference is the scales are different along the y axis.
Frequently it is not convenient to have the origin of the graph coincide with the
lower left hand corner of the coordinate paper. Full utilization of the paper with
suitable intervals is the one criteria for deciding how to plot a curve from the
experimental data. For example, the curve below (Figure 0-6) is poorly planned,
where the following (Figure 0-7) is a better way of representing the gas law
0 2 4 6 8 10
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35

y 0.1 x =
0 2 4 6 8 10
0
2
4
6
8
10
PV nRT =
Mathematics Review
FIGURE 0-6. Poorly presented graph
FIGURE 0-7. Well arranged graph
2.4.10 GRAPHS OF LOGARITHMIC FUNCTIONS
Previously variables were raised to constant powers; as . In this section
constants are raised to variable powers; as . Equations of this kind in which
the exponent is a variable are called (naturally) exponential equations. The most
important exponential equation is where is plotted against .
2.4.11 SEMILOGARITHMIC COORDINATES
Exponential or logarithmic equations are very common in physical chemical phe-
nomenon. One of the best ways of determining whether or not a given set of phe-
nomenon can be expressed by a logarithmic or exponential equation is to plot the
logarithm of one property against another property. Frequently a straight line is
obtained and its equation can be readily found. For example:
0 4 8 12 16 20
0
10
20
30
40
50

1 2 3 4 5 6 7 8 9 10
Pressure (atm)
0
5
10
15
20
25

y x
2
=
y 2
x
=
e
x
x
Mathematics Review
In the following table the plasma concentration of the immunosuppressant
cyclosporine was measured after a single dose (4mg/kg) as a function of time.
These can be illustrated in three different ways (Figures 0-8, 0-9, 0-10),
A. Concentration vs. time directly
B. Log concentration vs. time directly
C. Log concentration vs. time with concentration plotted directly on to logarithmic
scale of ordinates.
FIGURE 0-8. Concentration (ng/ml) vs. time (hr)
TABLE 2-12 Plasma concentration of cyclosporine
Time (hours)
Concentration
0.25 1900
.75 1500
1.5 1300
4 900
6 600
8 390
Dmello et al., Res. Comm. Chem. Path. Pharm. 1989: 64 (3):441-446
C
p
( )
ng
ml
------
200
400
600
800
1000
1200
1400
1600
1800
2000
0 1 2 3 4 5 6 7 8
Mathematics Review
FIGURE 0-9. Log Concentration vs. time
FIGURE 0-10. Log concentration (on log scale) vs. time
Graphing is much easier because the graph paper itself takes the place of a loga-
rithmic table, as shown in Figure 1-10.
Only the mantissa is designated by the graph paper. Scaling of the ordinate for the
characteristic is necessary. The general equation can be expressed as a
straight line by basic laws of indices.
Log Concentration - Time Curve
2.300
2.400
2.500
2.600
2.700
2.800
2.900
3.000
3.100
3.200
0 1 2 3 4 5 6 7 8
100
1000
10000
0 1 2 3 4 5 6 7 8
y Be
ax
=
y ln B ln e
ax
( ) ln + = y ln B ln ax + =
y ln ax B ln + =
Mathematics Review
One axis is printed with logarithmic spacing, and the other with arithmetic spac-
ing. It is used when a graph must be plotted as in the example (Figure 1-4)
and .
In this example, the vertical logarithmic axis is labelled Plasma concentration of
cyclosporine and the values plotted are the ordinary values of . Thus, there is
no need to use logarithmic tables, because the logarithmic spacing is responsible
for obtaining a straight line.
Two problems may occur when graphing on a logarithmic mantissa:
a) there are not enough cycles to incorporate all the data
b) obtaining the value of the slope is difficult. In this instance the slope is given by:
Hence, before calculating the value of m, the two selected values of and
must be converted, using a calculator, to and in order to satisfy the
equation. The same problem may arise in obtaining the intercept value, b.
The two problems may be avoided by plotting the same data on ordinary paper, in
which case the vertical axis is labelled log plasma concentration. However, in
this instance the ordinary values of must be converted to prior to plot-
ting. It is the values which are then plotted.
The calculation of the slope is direct in this case, as the values of and may be
read from the graph.
Hence, one must consider the relative merits of semilogarithmic and ordinary
paper before deciding which to use when a log plot is called for.
In the case of semilog graphs the slope may be found in a slightly different manner,
i.e., taking any convenient point on the line we usually take the as the second
point, one half of . Thus,
y C
p
[ ] log = x t =
C
p
[ ]
m
y
2
y
1
x
2
x
1
----------------
C
p
[ ]
2
ln C
p
[ ]
1
ln
t
2
t
1
-------------------------------------------- = =
C
p
[ ]
1
C
p
[ ]
2
C
p
[ ]
1
ln C
p
[ ]
2
ln
C
p
[ ] C
p
[ ] ln
C
p
[ ] ln
y
1
y
2
y
1
( )
y
2
( ) y
1
( )
m
y ln
1
1 2 ( )y
1
( ) ln
t
1
t
2
-----------------------------------------------
y
1
1 2 ( )y
1
--------------------
,
_
ln
t
1
t
2
-------------------------------
1
1 2
----------
,
_
ln
t
1
t
2
---------------------
2 ln
t
1
t
2
--------------
0.693
t
1 2
------------- = = = = =
Mathematics Review
(in which case, is called the half-life ). Since , then
because and .
2.4.12 LOG - LOG COORDINATES
Functions of the type give straight lines when plotted with logarithms
along both axis.
i.e., equation in logarithmic form is:
or
which is in the form
This is directly applicable to parabolic and hyperbolic equations previously dis-
cussed (see Figure 1-5).
2.4.13 PITFALLS OF GRAPHING: POOR TECHNIQUE
The utility of these procedures requires proper graphing techniques. The picture
that we draw can cause formation of conceptualizations and correlations of the
data that are inconsistent with the real world based simply on a bad picture. Conse-
quently the picture must be properly executed.
The most common error is improper axes labelling. On a single axis of rectilinear
coordinate paper (standard graph paper), a similar distance between two points
corresponds to a similar difference between 2 numbers. Thus,
t
2
t
1
t
t
1
t
2
< t
1
t
2
t
1 2
=
m
0.693
t
1 2
------------- k = = k
0.693
t
1 2
------------- =
y Bx
a
=
y log B log a x log + =
y log a x log b log + =
y mx b + =
Mathematics Review
FIGURE 0-11. Graphing using standard number spacing
FIGURE 0-12. Nonstandard (incorrect) graph
Obviously, the distance (Time) on the graph 12 between 0 and 2 hours should not
be the same as the distance between 10 and 20 hours. It is, and therefore Figure 0-
12 is wrong.
Similarly, the use of similar paper may result in some confusion. With logarithms
the mantissa for any string of numbers, differing only by decimal point placement,
is the same. What differentiates one number from another, in this case, is the char-
acteristic. Thus,
TABLE 2-13 Logarithmic graphing
Number Mantissa Characteristic Log
234 .3692 2 2.3692
23.4 .3692 1 1.3692
0 5 10 15 20 25 30
0
10
20
30
40
0
0
2 5 10 20 30
1
10
20
30
40
Mathematics Review
The paper automatically determines the relationship between strings of numbers
(mantissa) by the logarithmic differences between the numbers on the axis within a
cycle. The student must determine the order of magnitude (characteristic) to be rel-
egated to each cycle.
FIGURE 0-13. Logarithmic mantissa
Thus, we see, in Figure 0-13, the cycle on the semilog paper to relate to orders of
magnitude (e.g., 1, 10, 100, 1000, etc.) and consequently the characteristic of the
exponent.
The third common problem is labelling the log axis as log y. This is improper. It
is obvious from the spacing on the paper that this function is logarithmic, and thus
the axis is simply labelled y.
There are almost as many different errors as there are students and it is impossible
to list them all. These few examples should alert you to possible problems.
2.4.14 GRAPHICAL ANALYSIS
We will look at several different types of plots of data:
2.34 .3692 0 0.3692
0.234 .3692 -1 1.3692
TABLE 2-13 Logarithmic graphing
Number Mantissa Characteristic Log
234
23.4
2.34
0.234
1.0 1.5 2.0 2.5 3.0 3.5 4.0
X axis (units)
10
-1
10
0
10
1
10
2
10
3
Y

a
x
i
s

(
u
n
i
t
s
)

Logarithmic Plot
Mathematics Review
FIGURE 0-14. Straight line going down on semi-log paper
Find the slope by taking any two values on the Y axis such that the smaller value is
one half of the larger. The time that it takes to go from the larger to the smaller is
the half-life. Dividing 0.693 by the half-life yields the rate constant.
Extrapolating the line back to yields the intercept.
FIGURE 0-15. Curved line which plateaus on semi-log paper.
0 1 2 3 4 5
t 0 =
0 2 4 6 8 10 12
Mathematics Review
FIGURE 0-16. Curved line which goes up and then straight down on semi-log paper.
Find the terminal slope by taking any two values on the Y axis such that the
smaller value is one half of the larger. The time that it takes to go from the larger to
the smaller is the half-life. Dividing 0.693 by the half-life yields the rate constant.
Plot type one is reasonably easily evaluated. There are 2 important things that can
be obtained: Slope and Intercept. However, the slope and intercept have different
meanings dependent on the data set type plotted. The slope is the summation of all
the ways that the drug is eliminated, -K.
TABLE 2-14 Plot type 1
Data Type Y axis X axis Slope Intercept
IV Bolus Parent Drug Conc. parent compound Time -K
IV Bolus Parent
urine rate of excretion
parent compound
Time
(mid)
-K
IV Bolus Parent
Cumulative urine
data
Time -K
0 5 10 15 20 25
C
p0
dose
Vd
----------- =
dXu
dt
----------
Kr X
0
Xu
Xu kr
K X
0
--------------
Mathematics Review
Plot type two is not usually evaluated in its present form as only the plateau value
can be obtained easily. But again it has different meanings dependent on the data
plotted.
Usually urine data of this type (parent compound - IV bolus) is replotted and eval-
uated as plot 1 (above). Infusion data can be replotted using the same techniques,
but usually is not.
Plot type 3 must be stripped of the second rate constant from the early time points,
thus:
There are 3 things that can be obtained from the plot: the terminal slope (the
smaller rate constant), the slope of the stripped line (the larger rate constant) and
the intercept. The rate constants obtained from a caternary chain (drug moving
from one box to another in sequence in compartmental modeling) are the summa-
tion of all the ways that the drug is eliminated from the previous compartment and
all the ways the drug is eliminated from the compartment under consideration. See
LaPlace Transforms for further discussion.
Again, dependent on the data set type being plotted they will have different values.
TABLE 2-15 Plot Type 2
Data Type Y axis X axis Plateau Value
IV Bolus Parent
Cumulative urine
data parent compound
Time
IV Infusion
Parent
Drug concentration
parent compound
Time
TABLE 2-16 Plot Type 3
Data
Type Y axis X axis S1 S2 Intercept
IV Bolus
Parent
Metabolite conc. Time -K
small
-K
large
IV Bolus
Parent
excretion
rate of metabolite
into urine
Time
(mid)
-K
small
-K
large
Oral Drug conc. Time -K
small
-K
large
Xu
Xu
kr
K X
0
-------------- =
C
p
( )
ss
Q
K V
------------
Q
cl
---- = =
km X
0
K
l e arg
K
small
( ) V
dm
-------------------------------------------------------
dXmu
dt
---------------
k
mu
k
m
X
0

K
l e arg
K
small
------------------------------------
k
a
fX
0
K
l e arg
K
small
( ) V
d
----------------------------------------------------
Mathematics Review
2.5 Pharmacokinetic Modeling
It has been observed that, after the administration of a drug, the concentration of
the drug in the body appear to be able to be described by exponential equations.
Thus, it appears that, even though the processes by which the drug is absorbed. dis-
tributed, metabolized and excreted (ADME) may be very complex, the kinetics
(math) which mimics these processes is made up of relatively simple first order
processes and is called first order pharmacokinetics. A second observation is that
the resulting concentration is proportional to dose. When this is true, the kinetics is
called linear. When this math is applied to the safe and effective therapeutic man-
agement of an individual patient, it is called clinical pharmacokinetics. Thus, in
clinical pharmacokinetics, we monitor plasma concentrations of drugs and suggest
dosage regimens which will keep the concentration of drug within the desired ther-
apeutic range. Pharmacodynamics refers to the relationship between the drug con-
centration at the receptor and the intensity of pharmacological (or toxicological)
response. It is important to realize that we want to control the pharmacological
response. We do that indirectly by controlling the plasma concentration. In order
for this to work, we assume kinetic homogeneity, which is that there is a predict-
able relationship between drug concentration in the plasma (which we can mea-
sure) and drug concentration at the receptor site (which we can not measure). This
assumption is the basis for all clinical therapeutics.
Models are simply mathematical constructs (pictures) which seem to explain the
relationship of concentration with time (equations) when drugs are given to a per-
son (or an animal). These models are useful to predict the time course of drugs in
the body and to allow us to maintain drug concentration in the therapeutic range
(optimize therapy). The simplest model is the one used to explain the observations.
We model to summarize data, to predict what would happen to the patient given a
dosage regimen, to conceptualize what might be happening in disease states and to
compare products. In every case, the observations come first and the explanation
next. Given that a data set fits a model, the model can be used to answer several
different types of questions about the drug and how the patient handles the drug
(its disposition), for example: if the drug were to be given by an oral dose, how
much is absorbed and how fast? Are there things which might affect the absorp-
tion, such as food or excipients in the dosage form itself. What would happen if the
drug were to be given on a multiple dose regimen? What if we increased the dose?
etc.
You should be able to:
be facile in the use of the equations. You should be able to graphically manipulate data sets and
extract pharmacokinetic parameters, applying the appropriate equations or variations of them.
Mathematics Review
define all new words used in this section. e g.: Succinctly define, stating rigorously the meaning
of any symbols used and the dimensions of measurement.
compare and contrast new concepts used in this section. e. g.: rate and rate constant, zero and
first order kinetics, bolus and infusion methods, excretion and elimination, the assumptions
made in pharmacokinetic models with physiological reality. Why can these assumptions be
made?
pictorially represent any two variables (graph) one vs. the other. e.g. for each of the following
pairs of variables (ordinate against abscissa), draw a graph illustrating the qualitative profile of
their relationship. Where appropriate, indicate the nature of important slopes, intercepts, and
values. Unless you specifically indicate on your plot that semi-log paper is being considered
(write S-L), it will be assumed that rectilinear paper is being considered. Graphs are for a
drug given by IV Bolus where applicable.
2.5.1 MAKING A MODEL
The differential equations used result from the
model which is our conceptualization of what is
happening to the drug in the body.
The box (compartment) is the area of interest. We
want to find out how the mass of drug, , changes
with time in that compartment, the rate, and how the rates change with time, the
differential equations.
How do we make a dif-
ferential equation?
The picture that we build is made up of building blocks, consisting of the arrow
and what the arrow touches. The arrow demonstrates how quickly the mass of
drug, , declines. The arrow times the box that the arrow touches = the rate. Rates
can go in, i.e. arrows pointing to a box mean drug is going in (+ rate). Rates can go
out, i.e. arrows pointing away means drug is going out (- rate). Rate = rate constant
(arrow) times mass of drug (box). So the arrow and box really is a pictorial repre-
sentation of a rate where the rate is the rate constant on the top of the arrow times
what the tail of the arrow touches.
Again, the rate constant, , tells the magnitude of the rate, .
Consider the following simple chain:
X
k
a
X
X
k k X
X
1
X
3
X
2
k
12
k
23
Mathematics Review
The building blocks are and . Every arrow that touches the compart-
ment of interest becomes part of the differential equation. If the arrow goes to the
box, its positive; if it goes away from the box, its negative.
To find (the rate of change of with time), we simply add up all of the
rates which affect (all of the arrows that touch )
and thus:
(Note: the first subscript of the rate constant and the subscript of the box from
which it originates are the same.)
You should be able to develop the series of interdependent differential equations
which would result from any model. The integration of those equations by use of
the Laplace Table is done by transforming each piece of the equation into the
Laplace domain (looking it up on the table and substituting). The algebra per-
formed solves for the time dependent variable: put everything except the variable
(including the operator, s) on the right side and put the variable on the left. Find the
resulting relationship on the left side of the table. The corresponding equation on
the right side of the table in the integrated form.
You should be able to integrate any differential equation developed from any
model (within reason) that we can conceptualize.
(Note: Each subsequent variable is dependent on the ones that precedes it. In fact,
the solutions to the preceding variables are substituted into the differential to
remove all but one of the time dependent functions - the one that we are currently
attempting to solve.)
k
12
X
1
k
23
X
2
dX
1
dt X
1
X
1
X
1
dX
1
dt
--------- k
12
X
1
=
dX
2
dt
--------- k
12
X
1
k
23
X
2
=
dX
3
dt
--------- k
23
X
2
=
Mathematics Review
2.5.2 ONE COMPARTMENT OPEN MODEL
A simplified picture (mathematical construct) of the way the body handles drug is
one where the body can be conceived to be a rapidly stirred beaker of water (a sin-
gle compartment). We put the drug in and the rate at which the drug goes away is
proportional to how much is present (first order). Thus the assumptions are:
Body homogeneous (one compartment)
Distribution instantaneous
Concentration proportional to dose (linear)
Rate of elimination proportional to how much is there. (First order)
It is important to note that we know some of these assumptions are not true. It is of
little consequence, as the data acts as if these were true for many drugs. The visual
image which is useful is one of a single box and a single arrow going out of the
box depicting one compartment with linear kinetics. The dose is placed in the box
and is eliminated by first order processes. In many cases, more complicated mod-
els (more boxes) are necessary to mathematically mimic the observed plasma ver-
sus time profile when one or more of these assumptions are not accurate. For
example, the two compartment (or multi-compartment) model results when the
body is assumed to not be homogeneous and distribution is not instantaneous.
Mathematics Review
2.6 The LaPlace Transform
Why do we need to
know the LaPlace trans-
form?
One of the important facets of biopharmaceutics is a familiarity with the principles
of pharmacokinetics. This latter discipline describes the study of the dynamic pro-
cesses by which the body handles or disposes of an administered drug. These
processes (absorption, distribution, metabolism, and excretion (ADME) are
dynamic in that they represent the time-dependent changes occurring to the drug.
Thus, in pharmacokinetics the time course of these changes, which overall
describe the fate of the administered drug, is described mathematically. If the
mathematical principles are understood, it is then possible to use pharmacokinetics
in clinical practice, such as the design of rational dosage regimens (T.S. Foster and
D.U.A. Bourne, Amer. J. Hosp. Pharm., 34, 70-75 (1977). Understanding
(Blooms level 5) is not simply memorizing (Blooms level 1) nor calculating
using a memorized equation (Blooms level 3). The authors believe that the proper
conceptualizing of the process and the subsequent derivation of the appropriate
equations will lead to an understanding of the mathematical principles, and thus, a
better, more optimal dosing regimen.
Since a mathematical description of the time-dependent ADME processes is
required, it becomes necessary to deal with their corresponding rate equations.
Inevitably this will involve calculus (mainly integral calculus). However, the
LaPlace Transform provides a method whereby calculus can be performed with
minimal trauma. If a conscientious effort to learn the method is made and applied,
a potentially serious obstacle (the fear of calculus) to the understanding and appre-
ciation of biopharmaceutics will be removed. Indeed, many students will find they
no longer fear integration and are thus free to comprehend the principles underly-
ing pharmacokinetics, which, after all, is the primary aim. So, the LaPlace Trans-
form is a tool which is of great assistance in pharmacokinetics; its utility and
importance should not be lightly disregarded.
The LaPlace Trans-
form: What Is It?
There is, of course, a theoretical background to the LaPlace Transform. However,
it can be used without recourse to a complete theoretical discussion, though appro-
priate pharmaceutical use of the method is found in the following references:
M. Mayersohn and M. Gibaldi, Amer. J. Pharm. Ed., 34, 608-614 (1970).
M. Gibaldi and D. Perrier, Pharmacokinetics, Marcel Dekker, pp. 267-272
(1975).
Basically, the LaPlace Transform is used to solve (integrate) ordinary, linear differ-
ential equations. In pharmacokinetics such equations are zero and first-order rate
equations in which the independent variable is time. For instance, if a differential
equation describing the rate of change of the mass of drug in the body with time is
Mathematics Review
integrated, the final equation will describe the mass of drug actually in the body at
any time.
The procedure used is to replace the Independent variable (time) by a function
containing the LaPlace Operator, whose symbol is s. In doing so we have
replaced the time domain by a complex domain. This is analogous to replacing a
number by its logarithm. Once in the complex domain, the transformed function
may be manipulated by regular algebraic methods. Then the final expression in the
complex domain is replaced by its equivalent in the time domain, yielding the inte-
grated equation. This ultimate process is analogous to taking an antilogarithm.
2.6.1 TABLE OF LAPLACE TRANSFORMS
A table of useful LaPlace
transforms is given in
Section 2.7. Page 2-56.
The replacement of expressions in one domain by their equivalents in another is
accomplished by reference to tables. One column shows time domain expressions,
stated as , and second column shows the corresponding complex domain
expressions, stated as the LaPlace Transform. Note that simply means
some function of time. For example, when is , then the LaPlace
Transform is , where B is a constant and a is a rate constant
For example, when the LaPlace Transform is , then is .
2.6.2 SYMBOLISM
For simplicity in writing transformed rate expressions (and to distinguish them
from untransformed (time domain) expressions), the following symbolism will be
employed:
a bar will be placed over the dependent variable which is being transformed.
Example:
If X is the mass of unchanged drug in the body at any time, then X is the LaPlace
Transform of this mass.
f t ( )
f t ( )
f t ( ) Be
at
B s a + ( )
A s
2
f t ( ) At
Mathematics Review
2.6.3 CONVENTIONS USED IN DRAWING PHARMACOKINETIC SCHEMA.
When drugs enter the body, they will encounter many different fates. It is impor-
tant to set up the possible fates of the drug by creating a well thought out flow
chart or scheme in order to follow all the events that are occurring in the body as
described by the pharmacokinetic description of the drug. For example, a drug
may be excreted unchanged or may undergo hepatic metabolism to yield active or
inactive metabolites. All of these components are part of pharmacokinetics, which
by definition, includes ADME (the Absorption, Distribution, Metabolism and
Excretion of drugs), and must be considered. This flow chart becomes the back-
bone or the framework upon which to build the equations which describe the phar-
macokinetics of the drug. The differential equations result as a direct consequence
of the flow chart. Using Laplace transforms, the integration of these differential
equations are simplified and provide the pharmacokineticist to (easily?) keep track
of all of the variables in the equation. If the drug scheme or flow chart is set up
incorrectly, this would have a definite negative impact or the expected equations
(as well as the answers and your grade). Below are two examples of how to con-
struct a flow chart. Note that not all drugs follow the same flow chart and it is
quite possible that you will need only to use a portion of these examples when con-
struction your own.
In general, schema are relatively consistent in the placement of the compartments
in relationship to one another. You might consider, for example a drug, given by
IV bolus, which is metabolized and both the metabolite and the parent compound
are excreted unchanged as shown below:
X Xu Xf
Xm Xmu Xmf
Parent Compound
Metabolite
Feces Body Urine
ku kf
km
kmf kmu
Dose
Mathematics Review
Using the pharmacokinetic symbolism from chapter one, the compartments are
named and placed: metabolites below (or above the plane of the parent com-
pound): compounds going into the urine, to the right; and compounds going into
the feces, to the left of the compounds in the body. The rate constants connecting
the compartments also follow the symbolism from chapter one. In the above flow
chart, K1, the summation of all the ways that X is removed from the body, is ku +
kf + km while K2, the summation of all the ways that Xm is removed from the
body, is kmu +kmf.
Only those compartments are used which correspond to the drugs pharmacoki-
netic description, thus when a drug is given by IV bolus and is 100% metabolized
with the metabolite being 100% excreted into the urine the model would look like
this:
Thus in this flow chart, K1, the summation of all the ways that X is removed from
the body, is km while K2, the summation of all the ways that Xm is removed from
the body, is kmu.
X
Xm Xmu
km
kmu
Dose
Mathematics Review
Drugs sometimes are metabolized to two (or more) different metabolites. In the
first case, the drug is metabolized by two separate pathways resulting in this flow
chart:
In this flow chart, K1, the summation of all the ways that X is removed from the
body, is ku + kf + km1 + km2 while K2, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1 and K3, the summation of all the ways
that Xm2 is removed from the body, is kmu2 + kmf2.
While in a second case, the drug is metabolized and the metabolite is further
metabolized resulting in this flow chart:
X
Xm1
Xm2
km1
km2
Xmu1
Xu
Xmu2
ku
kmu1
kmu2 kmf2
kf
kmf1 Xmf1
Xf
Xmf2
Dose
X
Xm1
Xm2
km1
km2
Xmu1
Xu
Xmu2
ku
kmu1
kmu2 kmf2
kf
kmf1
Xmf1
Xf
Xmf2
Dose
Mathematics Review
In this flow chart, K1, the summation of all the ways that X is removed from the
body, is ku + kf + km1 while K2, the summation of all the ways that Xm1 is
removed from the body, is kmu1 +kmf1+ km2 and K3, the summation of all the
ways that Xm2 is removed from the body is kmf2 + kmu2.
Both of these flow charts result in very different end equations, so it is imperative
that the flow charts accurately reflect the fate of the drug.
2.6.4 STEPS FOR INTEGRATION USING THE LAPLACE TRANSFORM
Draw the model, connect the boxes with the arrows depicting where the drug goes.
The building blocks of the differential rate equations are the arrows and what the tail touches.
Write the differential rate equation for the box in question. The box is on the left side of the
equal sign and the building blocks are on the other. If the arrow goes away from the box, the
building block is negative, if it is going towards the box, the building block is positive.
Take the LaPlace Transform of each side of the differential rate equation, using the table where
necessary.
Algebraically manipulate the transformed equation until an equation having only one trans-
formed dependent variable on the left-hand side is obtained.
Convert the transformed expression back to the time domain, using the table where necessary to
yield the Integrated equation.
Mathematics Review
2.6.5 EXAMPLE INTEGRATION USING THE LAPLACE TRANSFORM
Following an intravenous injection of a drug (bolus dose), its excretion may be
represented by the following pharmacokinetic scheme:
(Scheme I)
Where is the mass of unchanged drug in the body at any time.
is the cumulative mass of unchanged drug in the urine up to any time, and is
the apparent first-order rate constant for excretion of unchanged drug.
Consider how the body excretes a drug
a. The building block is the arrow and what it touches. This first box (compart-
ment) of interest is . The arrow is going out, therefore, the rate is going out
and is negative, thus
(EQ 1-18)
The negative sign indicates loss from the body.
Taking the LaPlace Transform of each side of equation 1-18:
(EQ 1-19)
Note that because the independent variable (time) did not appear on the right-hand
side of equation 1-18, neither did the LaPlace Operator, s, appear there in equation
1-19. All that was necessary was to transform the dependent variable into .
Hence, the table was only required for transforming the left-hand side of equation
1-19.
Manipulating the transformed equation:
1. Get only one variable which changes with time
2. Get on the left and everything else on the right.
X X
u
k
u
X
X
u
k
u
X [ ] k
u
( )
dX
dt
------- k
u
X =
sX X
0
k
u
X =
X ( ) X
X ( )
X
Mathematics Review
(EQ 1-20)
(EQ 1-21)
Note that is the only transformed dependent variable and is on the left-hand side
of equation 1-20.
Converting back to the time domain:
(EQ 1-22)
Note that the right-hand side of equation 1-22 was analogous to in the
table, because is a constant (the initial dose administered). The left-hand side
of equation 1-22 could be converted back without the table.
The final expression is the familiar first-order integrated expression.
sX k
u
X + X
0
=
X s k
u
+ ( ) X
0
=
X
X
0
s k
u
+
------------- =
LetX
0
A = Letk
u
a = X
A
s a + ( )
---------------- =
X
X X
0
e
k
u
t
=
A
s a + ( )
----------------
X
0
Mathematics Review
2.6.6 SECOND EXAMPLE INTEGRATION USING THE LAPLACE
TRANSFORM
Look at Scheme I again. Consider how the drug goes from the body into the urine.
The next box of interest is . The arrow is coming in, therefore the rate is com-
ing in and is positive. thus,
(EQ 1-23)
(b) Taking the LaPlace Transform of each side of equation 1-23:
(EQ 1-24)
But, at zero time, the cumulative mass of unchanged drug in the urine was zero:
that is .
(EQ 1-25)
(c) Manipulating the transformed equation:
(EQ 1-26)
Note that there are two transformed dependent variables. One of them can be
replaced by reference to equation 1-20.
(EQ 1-27)
(EQ 1-28)
(d) Converting back to the time domain:
X
u
dX
u
dt
--------- k
u
X =
sX
u
X
u
( )
0
k
u
X =
X
u
( )
0
0 =
sX
u
k
u
X =
X
u
k
u
X
s
--------- =
X ( )
X
u
k
u
X
0
s s k
u
+ ( )
--------------------- =
Let k
u
X
0
( ) A = Let k
u
( ) a = X
A
s s a + ( )
------------------- =
X
u
k
u
X
0
1 e
k
u
t
( )
k
u
---------------------------------------- =
Mathematics Review
Where and are analogous to A and a respectively in the table. Sim-
plifying,
(EQ 1-29)
2.6.7 THIRD EXAMPLE INTEGRATION USING THE LAPLACE TRANSFORM
During the intravenous infusion of a drug, its excretion may be represented by the
following pharmacokinetic scheme:
(Scheme II)
Where Q is the zero-order infusion rate constant (the drug is entering the body at a
constant rate and the rate of change of the mass of drug in the body is governed by
the drug entering the body by infusion and the drug leaving the body by excretion).
The drug entering the body does so at a constant (zero-order) rate.
(EQ 1-30)
(b) Taking the LaPlace Transform of each side of equation 1-30:
Note that because Q is a rate, and is therefore a function of the independent vari-
able (time), its transformation yields the LaPlace Operator. In this case, Q was
analogous to A in the table. But, at zero time, the mass of unchanged drug in the
body was zero: that is,
(EQ 1-31)
(c) Manipulating the transformed equation:
(EQ 1-32)
k
u
X
0
k
u
X
u
X
0
1 e
k
u
t
( ) =
X X
u
k
u Q Infusion
dX
dt
------- Q k
u
X =
sX X
0
Q
s
---- k
u
X =
X
0
0 =
sX
Q
s
---- k
u
X =
X
Q
s s k
u
+ ( )
--------------------- =
Mathematics Review
(EQ 1-33)
(d) Converting back to the time domain:
(EQ 1-34)
2.6.8 CONCLUSIONS
The final integrations (Eqs. 24, 24, and 28) are not the ultimate goal of pharmaco-
kinetics. From them come the concepts of:
1. (a) elimination half-life
1. (b) apparent volume of drug distribution
2. (c) plateau drug concentrations
These, and other concepts arising from still other equations, are clinically useful.
Once the method of LaPlace Transforms is mastered, it becomes easy to derive
equations given only the required pharmacokinetic scheme. Under such circum-
stances, it no longer becomes necessary to remember a multitude of equations,
many of which, though very similar, differ markedly in perhaps one minute detail.
As with any new technique, practice is required for its mastery. In this case, mas-
tery will banish the calculus blues.
It is also possible to see certain patterns which begin to emerge from the derivation
of the equations. For example, for a drug given by IV bolus the equation is
monoexponential, with the exponent being K1, summation of all the ways that the
drug is removed form the body. A graph of the data (Cp v T on semi-log paper)
results in a straight line the slope of which is K1, always. If the drug is entirely
metabolized K1 = km. If the drug is entirely excreted unchanged into the urine,
K1 = ku. If the drug is metabolized and excreted unchanged into the urine, K1 =
km +ku. thus K1 can have different meanings for different drugs, depending on
how the body removes the drug. Following the drug given by IV bolus a second
example of a pattern would be that of the data of the metabolite of the drug. From
the LaPlace, the equation for the plasma concentration of the metabolite of the
drug has in it K1 and K2, the summation of all the ways that the metabolite is
removed from the body, always. K2 would have different meanings depending on
how the metabolite is removed from the body.
Let Q A = ( ) Let k
u
a = ( ) X
A
s s a + ( )
------------------- =
X
Q 1 e
k
u
t
( )
k
u
----------------------------- =
Mathematics Review
After several years teaching, I was fortunate to have a resident rotate through our
pharmacokinetic site. She had come with a strong Pharmacokinetcs background
and during our initial meeting, she had told me that she had a copy of John Wag-
ners new textbook on pharmacokinetcs. She was excited that, finally, there was a
compilation of all the equations used in pharmacokinetics in one place.
There are over 500 equations in the new book and I know every one, she said.
Im not sure which one goes with which situation, though. OOPS!
Throughout this text and on each exam, each equation is derived from first princi-
ples using scientific method, modeling and LaPlace Transforms in the hopes that
memorization will be minimized and thought (and consequently proper interpreta-
tion) would be maximized.
Mathematics Review
2.6.9 TABLE OF LAPLACE TRANSFORMS
are constants
are rate constants
is the LaPlace Operator
is a variable, dependent on time
is a power constant
A B ,
a b c , , a b c ( )
s
x t ( )
m
TABLE 2-17 Table of LaPlace Transforms
Time Function, LaPlace Transform, F t ( ) f s ( )
A A
s
---
At A
s
2
----
At
m
A m! ( )
s
m 1 +
---------------
Ae
at
A
s a +
-----------
At
m
e
at
A
s a + ( )
m 1 +
---------------------------
A 1 e
at
( )
a
--------------------------
A
s s a + ( )
-------------------
At
a
-----
A 1 e
at
( )
a
2
--------------------------
A
s
2
s a + ( )
---------------------
Ae
at B 1 e
at
( )
a
--------------------------
As B
s s a + ( )
-------------------
A
B
a
--- +
,
_
1 e
at
a
------------------
,
_
Bt
a
-----
As B
s
2
s a + ( )
---------------------
Mathematics Review
TABLE 2-17 Table of LaPlace Transforms
Time Function, LaPlace Transform, F t ( ) f s ( )
A e
bt
e
at
( )
a b ( )
---------------------------------
A
s a + ( ) s b + ( )
---------------------------------
A
a b ( )
----------------
1 e
bt
b
------------------
,
_
1 e
at
a
------------------
,
_
A
s s a + ( ) s b + ( )
------------------------------------
At
ab
------
A
a b ( )
----------------
1 e
bt
b
2
------------------
,

_
1 e
at
a
2
------------------
,

_

A
s
2
s a + ( ) s b + ( )
--------------------------------------
1
a b ( )
---------------- B Aa + ( )e
at
B Ab + ( )e
bt
[ ]
As B
s a + ( ) s b + ( )
---------------------------------
1
a b ( )
---------------- A e
bt
e
at
( ) B
1 e
bt
( )
b
----------------------
1 e
at
( )
a
----------------------

' ;

As B
s s a + ( ) s b + ( )
------------------------------------
1
a b ( )
---------------- A
B
b
--- +

' ;
1 e
bt
( )
b
---------------------- A
B
a
--- +

' ;
1 e
at
( )
a
----------------------
Bt
ab
------
As B
s
2
s a + ( ) s b + ( )
--------------------------------------
A
e
ct
a c ( ) b c ( )
---------------------------------
e
bt
a b ( ) c b ( )
---------------------------------
e
at
b a ( ) c a ( )
--------------------------------- + +
A
s a + ( ) s b + ( ) s c + ( )
--------------------------------------------------
A
1 e
ct
( )
c a c ( ) b c ( )
------------------------------------
1 e
bt
( )
b a b ( ) c b ( )
-------------------------------------
1 e
at
( )
a b a ( ) c a ( )
------------------------------------- + +
A
s s a + ( ) s b + ( ) s c + ( )
----------------------------------------------------
At
bc
------ A
1 e
ct
( )
c
2
a c ( ) b c ( )
--------------------------------------
1 e
bt
( )
b
2
a b ( ) c b ( )
---------------------------------------
1 e
at
( )
a
2
b a ( ) c a ( )
--------------------------------------- + +
A
s
2
s a + ( ) s b + ( ) s c + ( )
-------------------------------------------------------
dX
dt
-------
sX X
0
At
m 1 + ( )
m 1 + ( )
-------------------
A
s
m
-----
Mathematics Review
2.6.10 LAPLACE TRANSFORM PROBLEMS
By means of the LaPlace Transform, find the equation for:
1. The amount of drug in the body when the drug is given by IV Bolus (assume no metabolism).
2. The amount of drug in the urine when the drug is given by IV Bolus (assume no metabolism).
3. The amount of metabolite in the body when the drug is given by IV Bolus (assume no parent
drug excretion)
4. The amount of metabolite of the drug in the urine when the drug is given by IV Bolus (assume
no parent drug excretion)
5. The amount of metabolite of the drug in the urine when the drug is given by IV Bolus (assume
both parent drug and metabolite excretion)
6. The amount of drug in the body when the drug is given by IV infusion (assume no metabolism).
7. The amount of drug in the urine when the drug is given by IV infusion (assume no metabolism).
8. The amount of metabolite in the body when the drug is given by IV infusion (assume no parent
drug excretion).
9. The amount of metabolite in the urine when the drug is given by IV infusion (assume no parent
drug excretion).
10. The Rate of excretion of the metabolite into the urine for a drug given by IV bolus when
km+ku=kmu.
11. The amount of the principle metabolite (Xm1) when the drug is eliminated by several pathways
(Xu, Xm1,Xm2,Xm3,etc)
12. The concentration of drug, , in the body when the drug is given orally by a delivery system
which is zero order. What is the concentration at equilibrium ( ).
13. The amount of metabolite of a drug in the body when the drug is given by IV Bolus and con-
comitant IV infusion.
14. Disopyramide (D) is a cardiac antiarrythmic drug indicated for the suppression and prevention
of ectopic premature ventricular arrythmias and ventricular tachycardia. It appears that disopy-
ramide is metabolized by a single pathway to mono-dealkylated disopyramide (MND). In a
recent study, the pharmacokinetics of disopyramide were attempted to be elucidated by means
of a radioactive tracer. Since both D and MND would be labeled by the tracer, any equations
showing the time course of the label would show both the D and MND. By means of the
laPlace transform, find the equation for the rate of appearance of tracer into the urine if the drug
were given by IV Bolus.
X
V
d
------
T
Mathematics Review
2.6.11 LAPLACE TRANSFORM SOLUTIONS
1. The amount of drug in the body when the drug is given by IV bolus (assume no metabolism).
At time zero, all of the IV bolus is in the compartment.
Here K1 = ku

2. the amount of a drug in the urine when the drug is given by IV bolus (assume the drug is NOT metabolized
Again K1 = ku
X Xu ku
Dose
X X
o
=
dX
dt
------- k
u
X =
sX X
0
kuX =
sX kuX X
o
= +
X s k
u
+ ( ) X
o
=
X
X
o
s k
u
+
------------- =
Let X
0
( ) A k
u
a X
A
s a + ( )
---------------- = , = , = X X
o
e
kut
=
X Xu
ku
Dose
Mathematics Review
3. the amount of metabolite of a drug in the body
when the drug is given by IV bolus (assume no parent
drug excretion).
Here K1 = km and K2 = kmu
dX
u
dt
--------- k
u
X =
sX
u
X
uo
k
u
X =
sX
u
k
u
X =
sX
u
X
o
k
u
s k
u
+ ( )
------------------ =
X
u
X
o
k
u
s s k
u
+ ( )
--------------------- =
Let X
0
k
u
( ) A k
u
a = X
u
A
s s a + ( )
------------------- = , , =
X
u
k
u
X
o
1 e
kut
( )
k
u
------------------------------------- =
X
u
X
o
1 e
kut
( ) =
X
Xm Xmu
km
kmu
Dose
dx
dt
------ k
m
X =

or
in general terms.
NOTE: We could also:
and then
or
sX X
o
k
m
X =
sX k
m
X X
o
= +
X s k
m
+ ( ) X
o
=
X
X
o
s k
m
+
-------------- =
Let X
0
( ) A k
m
a X
A
s a + ( )
---------------- = , = , =
X X
o
e
kmt
=
dX
m
dt
---------- k
m
X = k
mu
X
m
sX
m
X
m0
k
m
X k
mu
X
m
=
sX
m
k
m
X
0
s k
m
+
-------------- k
mu
X
m
=
X
m
k
m
X
o
s k
mu
+ ( ) s k
m
+ ( )
------------------------------------------ =
Let k
m
X
0
( ) A k
m
a K1 k
mu
b K2 = = , = = , =
X
m
A
s a + ( ) s b + ( )
--------------------------------- =
X
m
k
m
X
o
( )
k
m
k
mu
( )
------------------------- e
k
mu
t
e
k
m
t
( ) =
X
m
k
m
X
o
( )
K1 K2 ( )
------------------------- e
K 2t
e
K 1t
( ) =
Let k
m
X
0
( ) A k
m
b k
mu
a = , = , =
X
m
k
m
X
o
( )
k
mu
k
m
( )
------------------------- e
k
m
t
e
k
mu
t
( ) =
Mathematics Review
Both of those equations are identical.
4. the amount of metabolite of a drug in the urine
when the drug is given by IV bolus (assume the parent
compound is not excreted).
Here, again, K1 = km and K2 = kmu

substitute previously solved

X
m
k
m
X
o
( )
K2 K1 ( )
------------------------- e
K 1t
e
K2t
( ) =
X
Xm Xmu
km
kmu
Dose
dXm
dt
----------- k
m
X k
mu
X
m
=
sX
m
X
om
k
m
X k
mu
X
m
=
sX
m
k
mu
Xm k
m
X = +
X
X
o
s k
m
+
-------------- =
X
m
s k
mu
+ ( )
k
m
X
o
s k
m
+
-------------- =
X
m
k
m
X
o
s k
mu
+ ( ) s k
m
+ ( )
------------------------------------------ =
X
m
k
m
X
o
e
kmt
e
kmut
( )
k
mu
k
m
( )
--------------------------------------------------- =

Remember at time zero,

5. the amount of metabolite of a drug excreted in
the urine when both the parent and metabolite are
excreted.
Here K1 = km + ku and K2 = kmu

dX
mu
dt
------------- k
mu
X
m
=
sX
mu
X
om
k
mu
X
m
=
X
om
0 =
sX
mu
k
mu
X
m
=
sX
mu
k
mu
( ) k
m
X
o
( )
s k
mu
+ ( ) s k
m
+ ( )
------------------------------------------ =
X
mu
k
mu
( ) k
m
( ) X
o
( )
s s k
mu
+ ( ) s k
m
+ ( )
--------------------------------------------- =
X
mu
k
mu
k
m
X
o
k
mu
k
m
---------------------
1 e
kmt
k
m
---------------------
1 e
kmut
k
mu
-----------------------
,

_
=
X
Xm Xmu
km
kmu
Dose
Xu ku
dX
dt
------- k
u
X k
m
X =
sX X
o
k
u
X k
m
X =
Mathematics Review
6. The amount of drug in the body from a drug given by
IV infusion (assume no metabolism).
sX k
u
X k
m
X X
o
= + +
X s k
u
k
m
+ + ( ) X
o
=
k
u
k
m
+ ( ) K1 =
X
X
o
s K1 +
---------------- =
X X
o
e
K1t
=
dXm
dt
------------ k
m
X k
mu
X
m
k
m
X K2X
m
= =
sX
m
X
om
k
m
X K2X
m
=
sX
m
K2Xm k
m
X = +
X
m
k
m
X
o
s K2 + ( ) s K1 + ( )
------------------------------------------ =
dX
mu
dt
------------- k
mu
X
m
=
sX
mu
X
om
k
mu
X
m
K2Xm = =
sX
mu
K2X
m
=
sX
mu
k
mu
( ) kmX
o
( )
s K2 + ( ) s K1 + ( )
------------------------------------------ =
X
mu
k
mu
( ) k
m
( ) X
o
( )
s s K2 + ( ) s K1 + ( )
-------------------------------------------- =
X
mu
k
mu
k
m
X
o
K2 K1
----------------------
1 e
K1t
K1
---------------------
1 e
K2t
K2
---------------------
,
_
=
At time zero, all the drug is still in the IV bag, therefore
there is no drug in the body. X
0
= 0
Here K1 = ku
or
7. the amount of drug in the urine when the drug is
given by infusion (assume the drug is NOT metabolized).
Here K1 = ku
X Xu ku
Q
dX
dt
------- Q k
u
X =
sX X
0
Q
s
---- K
u
X =
sX k
u
X +
Q
s
---- =
X
Q
s s k
u
+ ( )
--------------------- =
X
Q
k
u
----- 1 e
k
u
t
( ) =
X
Q
K1
------- 1 e
K1t
( ) =
X Xu ku
Q
dX
dt
------- Q k
u
X =
sX X
o
Q
s
---- k
u
X =
sX k
u
X
Q
s
---- = +
Mathematics Review
or
8. the amount of metabolite of a drug in the body
from a drug given by IV infusion (assume no parent drug
excretion) Here K1 = km and K2 = kmu
.
X s k
u
+ ( )
Q
s
---- =
X
Q
s s k
u
+ ( )
------------------------- =
dX
u
dt
--------- k
u
X =
sX
u
X
o
k
u
X =
sX
u
k
u
X =
sX
u
k
u
Q
s s k
u
+ ( )
------------------------- =
X
u
k
u
Q
s
2
s k
u
+ ( )
---------------------------- =
X
u
k
u
Qt
k
u
----------- Qk
u
1 e
kut
k
u
2
--------------------
,

_
=
X
u
Qt Q
1 e
kut
( )
k
u
------------------------- = X
u
Qt Q
1 e
K1t
( )
K1
-------------------------- =
X
Xm Xmu
km
kmu
Q
or
9. the amount of metabolite of a drug in the urine
from a drug given by IV infusion (assume that the parent
compound is not excreted). Here K1 = km and K2 = kmu
dX
dt
------- Q k
m
X =
sX X
o
Q
s
---- k
m
X =
sX k
m
X
Q
s
---- = +
X s k
m
+ ( )
Q
s
---- =
X
Q
s s k
m
+ ( )
---------------------- =
X Q
1 e
kmt
( )
k
m
-------------------------- =
dX
m
dt
---------- k
m
X k
mu
X
m
=
sX
m
X
o
k
m
X k
mu
X
m
=
sX
m
k
m
X k
mu
X
m
=
X
m
k
m
Q
s s k
mu
+ ( ) s k
m
+ ( )
--------------------------------------------- =
X
m
A
a b ( )
---------------- =
1 e
bt
b
------------------
,
_
1 e
at
a
------------------
,
_
X
m
k
m
Q
k
mu
k
m
( )
------------------------- =
1 e
k
m
t
k
m
--------------------
,

_
1 e
k
mu
t
k
mu
---------------------
,

_
X
m
k
m
Q
K2 K1 ( )
------------------------- =
1 e
K1t
K1
---------------------
,
_
1 e
K2t
K2
---------------------
,
_

Mathematics Review
X
Xm Xmu
km
kmu
Q
dX
dt
------- Q k
m
X =
sX X
o
Q
s
---- k
m
X =
sX k
m
X
Q
s
---- = +
X s k
m
+ ( )
Q
s
---- =
X
Q
s s k
m
+ ( )
---------------------- =
dX
m
dt
---------- k
m
X k
mu
X
m
=
sX
m
X
o
k
m
X k
mu
X
m
=
sX
m
k
mu
X
m
k
m
X = +
X
m
s k
mu
+ ( )
k
m
Q
s s k
m
+ ( )
---------------------- =
X
m
k
m
Q
s s k
m
+ ( ) s k
mu
+ ( )
--------------------------------------------- =
X
m
k
m
Q
k
m
k
mu
--------------------
1 e
kmut
k
mu
-----------------------
,

_
1 e
kmt
k
m
---------------------
,

_
=
dX
mu
dt
------------- k
mu
X
m
=
substitute
or
10. the rate of excretion of the metabolite into the
urine for a drug given by IV bolus when
In this case, K1 = ku +km and K2 = kmu and thus K1 =
K2. This is not normal but could happen. The problem
arises when we get to the LaPlace that assumes the rate
constants are different (i.e. ) because for this special
case .
.
sX
mu
X
omu
k
mu
X
m
= X
m
X
mu
k
mu
k
m
Q
s
2
s k
m
+ ( ) s k
mu
+ ( )
----------------------------------------------- =
X
mu
k
mu
k
m
Qt
k
m
k
mu
----------------------
k
mu
k
m
Q
k
m
k
mu
---------------------
,
_
1 e
kmut
( )
k
2
mu
-----------------------------
1 e
kmt
( )
k
2
m
--------------------------
,

_
=
X
mu
k
mu
k
m
Qt
K1 K2
----------------------
k
mu
k
m
Q
K1 K2
--------------------
,
_
1 e
K2t
( )
K2
2
--------------------------
1 e
K1t
( )
K1
2
--------------------------
,

_
=
k
m
k
u
+ k
mu
=
a b
a b =
X
Xm Xmu
km
kmu
Dose
Xu ku
dX
dt
------- k
u
X k
m
X =
sX X
o
k
u
X k
m
X =
sX k
u
X k
m
X X
o
= + +
Mathematics Review

(remember- K2 = K1)
(k
m
X
0
= A)

X s k
u
k
m
+ + ( ) X
o
=
X
X
o
s k
u
k
m
+ + ( )
------------------------------- =
K1 k
u
k
m
+ ( ) =
k
mu
K2 =
X
X
o
s K1 + ( )
-------------------- =
X X
o
e
K1t
=
dX
m
dt
---------- k
m
X k
mu
X
m
( ) =
sX
m
X
om
k
m
X K2X
m
( ) =
sX
m
K2X
m
k
m
X = +
X
m
s K2 + ( )
k
m
X
o
s K +
------------ =
X
m
k
m
X
o
s K2 + ( ) s K1 + ( )
------------------------------------------ =
X
m
k
m
X
o
s K1 + ( ) s K1 + ( )
------------------------------------------ =
X
m
k
m
X
o
s K1 + ( )
2
----------------------- =
X
m
k
m
X
o
te
K1t
=
dX
mu
dt
------------- k
mu
X
m
=
dX
mu
dt
------------- k
mu
k
m
X
o
te
K1t
=
11. the principal metabolite when the drug is
cleared by several pathways
In this case K1 = km1 + km2 + ku, K2 = kmu1 and K3 =
kmu2

Let K1 = ku + km1 + km2

and

X
m1
( )
X
u
X
m1
X
m2
, , ( )
X
Xm1
Xm2
km1
km2
Xmu1
Xu
Xmu2
ku
kmu1
kmu2
Dose
dX
dt
------- k
u
X k
m1
X k
m2
X =
sX X
o
k
u
X k
m1
X k
m2
X =
sX k
u
X k
m1
X k
m2
X X
o
= + + +
X s k
u
k
m1
k
m2
+ + + ( ) X
o
=
X
X
o
s K1 + ( )
-------------------- =
K1 k
u
k
m1
k
m2
+ + ( ) = K2 k
mu1
=
dX
m1
dt
------------- k
m1
X K2X
m1
=
sX
m1
X
m1o
k
m1
X K2X
m1
=
X
m1o
0 =
sX
m1
K2X
m1
k
m1
X
o
s K1 + ( )
-------------------- = +
Mathematics Review

12. the concentration of drug in the body
when the drug is given orally by a delivery system which
is zero order. What is the concentration in the body at
equilibrium
Here K1 = ku

X
m1
s K2 + ( )
k
m1
X
o
s K1 + ( )
-------------------- =
X
m1
k
m1
X
o
s K1 + ( ) s K2 + ( )
------------------------------------------ =
X
m1
k
m1
X
o
K2 K1
-------------------- e
K1t
e
K2t
( ) =
X Vd
t
( )
X
Xu
ku Q
Xa
ka
dX
a
dt
--------- Q k
a
X
a
=
sX
a
X
ao
Q
s
---- k
a
X
a
=
X
a0
0 =
sX
a
k
a
X
a
Q s ( ) = +
X
a
s k
a
+ ( ) Q s ( ) =
X
a
Q
s s k
a
+ ( )
--------------------- =
X
a
Q 1 e
kat
( )
k
a
----------------------------- =
dX
dt
------- k
a
X
a
K1X =
sX X
o
k
a
X
a
k1X =

If t= , then , thus
simplified yields:
13 the metabolite of a drug in the body given
by IV infusion and concomitant IV bolus dose.
Infusion:
Here K1 = km and K2 = kmu
X
o
0 =
sX K1X
k
a
Q
s s k
a
+ ( )
--------------------- = +
X s K1 + ( )
k
a
Q
s s k
a
+ ( )
--------------------- =
X
k
a
Q
s s k
a
+ ( ) s K1 + ( )
------------------------------------------ =
X
k
a
Q
k
a
K1 ( )
-----------------------
1 e
K1t
) (
K1
---------------------------
1 e
kat
( )
k
a
-------------------------

' ;

=
C
k
a
Q
k
a
K1 ( )Vd
------------------------------
1 e
K1t
) (
K1
---------------------------
1 e
kat
( )
k
a
-------------------------

' ;

=
e
kt
0 = C
k
a
Q
k
a
K1 ( )Vd
------------------------------
1
K1
-------
1
k
a
-----

' ;

=
C
Q
K1Vd
-------------- =
Xm
X
Xm Xmu
km
kmu
Q
Dose
Mathematics Review
IV Bolus:
dX
dt
------- Q K1X =
sX X
o
Q
s
---- K1X =
sX K1X
Q
s
---- = +
X s K1 + ( )
Q
s
---- =
X
Q
s s K1 + ( )
----------------------- =
dX
m
dt
---------- k
m
X K2X
m
=
sX
m
X
o
k
m
X K2X
m
=
sX
m
K2X
m
k
m
X = +
X
m
s K2 + ( )
k
m
Q
s s K1 + ( )
----------------------- =
X
m
k
m
Q
s s K1 + ( ) s K2 + ( )
-------------------------------------------- =
X
m
k
m
Q
K2 K1 ( )
-------------------------
1 e
K1t
( )
K1
--------------------------
1 e
K2t
( )
K2
--------------------------

' ;

=
dX
dt
------- K1X =
sX X
o
K1X =
sX K1X X
o
= +
X s K1 + ( ) X
o
=
X
X
o
s K1 +
---------------- =
Thus,

14. By means of the LaPlace transform, find the
equation for the rate of appearance of the tracer in the
urine if the drug were given by IV bolus.
Here K1 = ku + km and K2 = kmu
dX
m
dt
---------- k
m
X K2X
m
=
sX
m
X
o
k
m
X K2X
m
=
sX
m
K2X
m
k
m
X = +
X
m
s K2 + ( )
k
m
X
o
s K1 +
---------------- =
X
m
k
m
X
o
s K1 + ( ) s K2 + ( )
------------------------------------------ =
X
m
k
m
X
o
K1 K2 ( )
------------------------- e
K2t
e
K 1t
( ) =
X
m
k
m
X
o
K1 K2 ( )
------------------------- e
K2t
e
K 1t
( )
,
_
below + =
k
m
Q
K1 K2
--------------------
1 e
K2t
( )
K2
--------------------------
1 e
K1t
( )
K1
--------------------------

' ;

,

_
X
Xm Xmu
km
kmu
Dose
Xu ku
Mathematics Review
dX
dt
------- k
u
X k
m
X =
sX X
o
k
u
X k
m
X =
sX k
u
X k
m
X X
o
= + +
X s k
u
k
m
+ + ( ) X
o
=
k
u
k
m
+ ( ) K1 =
X
X
o
s K1 + ( )
-------------------- =
X X
o
e
K1t
=
dX
u
dt
--------- k
m
X k
u
X
o
e
K1t
( ) = =
dX
m
dt
---------- k
m
X K2X
m
=
sX
m
X
o
k
m
X k2X
m
=
sX
m
K2X
m
k
m
X
o
s K1 + ( )
-------------------- = +
X
m
s K2 + ( )
k
m
X
o
s K1 +
---------------- =
X
m
k
m
X
o
s K2 + ( ) s K1 + ( )
------------------------------------------ =
X
m
k
m
X
o
K2 K1 ( )
------------------------- e
K1t
e
K2t
{ } =
dX
mu
dt
------------- k
mu
X
m
k
mu
k
m
X
o
K2 K1 ( )
------------------------- e
K1t
e
K2t
{ } = =
dX
u
dt
---------
dX
mu
dt
------------- k
u
X
o
e
K1t
( )
k
mu
k
m
X
o
K2 K1 ( )
-------------------------
,
_
e
K1t
e
K2t
{ } +
,
_
= +
CHAPTER 3 Pharmacological Response
OBJECTIVES
After completing this chapter, the student will be able to:
1. Given patient data of the following types, the student will be able to properly con-
struct (III) a graph and compute (III) the slope using linear regression: response
(R) vs. concentration (C), response (R) vs. time (T), concentration (C) vs. time (T)
2. Given any two of the above data sets, the student will be able to compute (III) the
slope of the third by linear regression.
3. Give response vs. time and response versus concentration data, the student will be
able to compute (III) the terminal (elimination) rate constant and half life of the
drug.
Pharmacological Response
3.1 Pharmacological Response
Drug must get into blood
and blood is in contact
with receptor.
One theory (A.J. Clarke) on the mechanism of action of drugs is the occupation
theory. It suggests that the intensity of a pharmacological response (E) is propor-
tional to the concentration of a reversible drug-receptor complex
3.1.1 THE HYPERBOLIC RESPONSE EQUATION
A mathematical description of the occupation theory, assuming complete and
instantaneous drug distribution, yields
(EQ 1-35)
where E is the intensity of the pharmacological response, is the maximum
attainable value of , is the molar concentration of free drug at the active com-
plex and is the dissociation constant of the drug-receptor complex.
If is plotted against a hyperbolic curve will result; the asymptote will be
.
a. If linear pharmacokinetics hold, the molar concentration of free drug at the
active site is proportional to the plasma concentration of the drug once equilibrium
has been established. Hence, a plot of against will also be hyperbolic.
b. Because the mass of drug in the body is , a plot of against will be
hyperbolic.
c. For a series of doses the value of at the same given time after dosing is propor-
tional to the dose (D). Thus, a plot of against D will also be hyperbolic at a spe-
cific time.
d. Any hyperbolic curve, if plotted on reverse semilogarithmic paper (i.e., abscissa
is logarithmic), has a sigmoid shape. If we plot against (of , or ) in this
manner, the plot is virtually linear in the range ; and if this is the
clinical range of responses, linear equations may be written. For example,
where is the slope
E
D [ ]E
max
K
R
D [ ] +
---------------------- =
0.0 0.8 1.6 2.4 3.2 4.0
D
PKAnalyst Plot
E
0.0
0.2
0.4
0.6
0.8
1.0
E
max
E D [ ]
K
R
E D [ ]
E
max
E C
p
X V C
p
= E X
X
E
E C
p
X D
E E
max
0.2 0.8 =
E m x ln b + =
m
10
-8
10
-7
10
-6
10
-5
10
-4
10
-3
10
-2
10
-1
Conc.
0.0
0.2
0.4
0.6
0.8
1.0
R
e
s
p
o
n
s
e

Plot of Response vs.
Ln(C) is a straight line in
the middle (if you
squint), but only
between 20% and 80%
maximum response
This example equation shows that, in the clinical range, the intensity of a pharma-
cological response is proportional to the logarithm of the administered dose, pro-
viding response is measured at a consistent time after dosing. The proportionality
constant (slope, ) is a function of the affinity of the drug for the receptor. In fact,
equation yields a log-dose response plot. Note that doubling the dose does not
double the response.
3.1.2 INTERRELATIONSHIPS BETWEEN CONCENTRATION, TIME AND
RESPONSE
Pharmacological Response (R), Concentration (C), and Time (t) are interrelated.
The response and concentration relationship is studied in pharmacology. The con-
centration and time relationship is studied in pharmacokinetics. The response and
time relationship is applied in therapeutics.
Remember: Use only
the data between 20%
and 80% of maximum
response for the straight
part of both response
vs. Ln(c) and response
vs. t.
You should know what the various graphical relationships look like. Response vs.
natural log of concentration is sigmoidal. (S shaped). We are interested in the mid-
dle almost straight part. The slope is .
Response vs. time is a straight line. The slope is .
Natural log of concentration vs. time (drug given by IV bolus) is a straight line.
The slope is .
You should be able to obtain the slope of each of these relationships from data sets.
You should be able to obtain the third slopes relationship given the other two (or
data sets with which to get the other two).
(EQ 1-36)
(EQ 1-37)
(EQ 1-38)
NOTE: Only between
20% and 80% of maxi-
mum response!!!!!!
You should be able to apply the equation to each of the above relation-
ships. Given the slope (or having obtained the slope) and two of the three variables
(y, x, b), you should be able to find the third.
m
dR d c ln
dR dt
d c dt ln
dR
dt
-------
dR
d c ln
-----------
d c ln
dt
----------- =
dR
d c ln
-----------
dR dt
d c ln dt
-------------------- =
d c ln
dt
-----------
dR dt
dR d c ln
---------------------- =
y mx b + =
3.2 Change in Response with Time
3.2.1 ONE-COMPARTMENT OPEN MODEL: INTRAVENOUS BOLUS
INJECTION
(EQ 1-39)
or
(EQ 1-40)
Substituting twice from eq. once at time t and once at zero time
(EQ 1-41)
Hence a plot of the intensity of the pharmacological response at any time
against time declines linearly. The slope is and the intercept is (the
initial intensity).
3.2.2 ONE-COMPARTMENT OPEN MODEL: ORAL ADMINISTRATION
Response follows
plasma profile.
Because is proportional to at any time, a plot of against will be analo-
gous to a plot of against . Hence will rise at first and then decline with time.
When is large, the terminal slope will be .
3.2.3 DURATION OF EFFECTIVE PHARMACOLOGICAL RESPONSE
Duration of action is
related to how long
plasma concentration is
above Minimum Effec-
tive Concentration.
Once equilibrium has been established, there is a minimum plasma concentration
below which no pharmacological response is seen; this concentration is or
. For an intravenous bolus injection, the time to reach is .
multiplying by the volume of distribution we obtain
(EQ 1-42)
Rearranging,
X X
0
e
Kt
De
Kt
= =
Ln X ( ) Ln D ( ) Kt =
E b
m
------------
E
0
b
m
--------------- Kt = E E
0
Rt =
E ( )
R K m ( ) = E
0
E x ln E t
x ln t E
t R
t
dur
( )
C
p
( )
eff
MEC C
p
( )
eff
t
dur
C
p
( )
eff
C
p
( )
0
e
Kt
dur
=
X
eff
( ) ln D ( ) ln Kt
dur
=
(EQ 1-43)
The duration of effective pharmacological response is proportional to the (natural)
logarithm of the dose. A second rearangement of equation 1-42 results in :
(EQ 1-44)
Thus a plot of duration of action vs ln dose would result in a straight line with a
slope of 1/K and an x intercept of .
3.2.4 PHARMACOKINETIC PARAMETERS FROM RESPONSE DATA
How can I get the elimi-
nation rate constant
from pharmacological
data? Use this cook-
book.
The measurement of pharmacological effect provides a non-invasive means of
obtaining the value of (but not ).
a. Obtain a log dose-response plot (Eq. 1-37). The response must always be mea-
sured at the same time after administering the dose.
Remember: Use only
the data between 20%
and 80% of maximum
Response for both of
these plots.
b. Find the slope of this plot.
c. Obtain a response against time plot for a single dose (Eq. 1-36).
d. Find the terminal slope of this plot.
e. Calculate .
f. Calculate .
3.2.5 DELAYED RESPONSE
Two compartment
model - biophase is in
second compartment.
If a drug does not distribute instantaneously to all the body tissues (including the
active site), the pharmacological response will not always parallel the drug con-
centrations in the plasma. In such a situation the response may parallel the mass of
drug presumed to be in a second compartment , and hence seem delayed.
Eventually, however, once equilibrium is attained, the response will parallel
plasma concentrations. In such a case, is proportional to .
t
dur
D
X
eff
--------
,
_
ln
K
-------------------- =
t
dur
Dose ( ) ln
K
-----------------------
X
eff
( ) ln
K
------------------- =

X
eff
( ) ln
K
-------------------
t
1 2
V
m ( )
R ( )
K
R
m
---- =
t
1 2
0.693
K
-------------
,
_
=
X
2
( )
E X
2
ln
Thus a plot of against (or against ) will show a hysteresis loop with time,
most noticeably during an intravenous infusion.
3.2.6 RESPONSE OF ACTIVE METABOLITE:
Parent compound (inac-
tive) yields active
daughter compound.
In the case of an inactive prodrug yielding an active metabolite, the response
curves will mirror the active metabolite plasma profile (assuming the biophase is
the plasma) and not the prodrug plasma profile.
E X
1
E C
p
3.3 Therapeutic Drug Monitoring
Part of Pharmaceutical
Care!
The pharmacokinetics of a drug determine the blood concentration achieved from
a prescribed dosing regimen. During multiple drug dosing, the blood concentration
will reflect the drug concentration at the receptor site; and it is the receptor site
concentration that determines the intensity of the drugs effect. Therefore, in order
to predict a patients response to a drug regimen, both the pharmacokinetics and
pharmacological response characteristics of the drug must be understood. Phar-
macological response is closely related to drug concentration at the site of action.
We can measure plasma concentration and assume that the site of action is in rapid
equilibrium with the plasma since we usually do not measure drug concentration in
the tissue or at the receptor site. This assumption is called kinetic homogeneity
and is the basis for clinical pharmacokinetics.
Need to keep plasma
concentration in the
therapeutic range to
optimize therapy.
There exists a fundamental relationship between drug pharmacokinetics and phar-
macologic response. The relationship between response and ln-concentration is
sigmoidal. A threshold concentration of drug must be attained before any response
is elicited at all. Therapy is achieved when the desired effect is attained because
the required concentration has been reached. That concentration would set the
lower limit of utility of the drug, and is called the Minimum Effective Concentra-
tion (MEC). Most drugs are not clean, that is exhibit only the desired therapeu-
tic response. They may also exhibit undesired side effects, sometimes called toxic
effects at a higher, (hopefully a lot higher), concentration. At some concentration,
these toxic side effects become become intolerable/and or dangerous to the
patient.. That concentration, or one below it, would set the upper limit of utility
for the drug and is called the Maximum Therapeutic Concentration or Minimum
Toxic Concentration (MTC). Patient studies have generated upper (MTC) and
lower (MEC) plasma concentration ranges that are deemed safe and effective in
treating specific disease states. These concentrations are known as the therapeutic
range for the drug (Table 2-18).
When digoxin is administered at a fixed dosage to numerous subjects, the blood
concentrations achieved vary greatly. Clinically, digoxin concentrations below 0.8
will elicit a subtherapeutic effect. Alternatively, when the digoxin concen-
tration exceeds 2.0 side effects occur (nausea and vomiting, abdominal pain,
visual disturbances). Drugs like digoxin possess a narrow therapeutic index
because the concentrations that may produce toxic effects are close to those
ng ml
ng ml
required for therapeutic effects. The importance of considering both pharmacoki-
netics and pharmacodynamics is clear.
Note that drug concentrations may be expressed by a variety of units.
Pharmacokinetic factors that cause variability in plasma drug concentration are:
drug-drug interactions
patient disease state
physiological states such as age, weight, sex
drug absorption variation
differences in the ability of a patient to metabolize and eliminate the drug
If we were to give an identical dose of drug to a large group of patients and then
measure the highest plasma drug concentration we would see that due to individual
variability, the resulting plasma drug concentrations differ. This variability can be
attributed to factors influencing drug absorption, distribution, metabolism, and
excretion. Therefore, drug dosage regimens must take into account any disease
altering state or physiological difference in the individual.
Therapeutic drug monitoring optimizes a patients drug therapy by determining
plasma drug concentrations to ensure the rapid and safe drug level in the therapeu-
tic range.
Two components make
up the process of
therapeutic drug
monitoring:
Assays for determination of the drug concentration in plasma
Interpretation and application of the resulting concentration data to develop a safe and effective
drug regimen.
TABLE 2-18 Average therapeutic drug concentration
DRUG RANGE
digoxin
0.8-2.0
gentamicin
2-10 l
lidocaine
1-4
lithium
0.4-1.4
phenytoin
10-20
phenobarbitol
10-30
procainamide
4-8
quinidine
3-6
theophylline
10-20
ng ml
g ml
g ml
mEq L
g ml
g ml
g ml
g ml
g ml
The major potential advantages of therapeutic drug monitoring are the maximiza-
tion of therapeutic drug benefits and the minimization of toxic drug effects. The
formulation of drug therapy regimens by therapeutic drug monitoring involves a
process for reaching dosage decisions.
3.3.1 THERAPEUTIC MONITORING: WHY DO WE CARE?
The usefulness of a drugs concentration vs. time profile is based on the observa-
tion that for many drugs there is a relationship between plasma concentration and
therapeutic response. There is a drug concentration below which the drug is inef-
fective, the Minimum Effective Concentration (MEC), and above which the drug
has untoward effects, the Minimum Toxic Concentration (MTC). That defines the
range in which we must attempt to keep the drug concentration (Therapeutic
Range).
The data in Table 2-18 are population averages. Most people respond to drug con-
centrations in these ranges. There is always the possibility that the range will be
different in an individual patient.
For every pharmacokinetic parameter that we measure, there is a population aver-
age and a range. This is normal and is called biological variation. People are differ-
ent. In addition to biological variation there is always error in the laboratory assays
that we use to measure the parameters and error in the time we take the sample.
Even with these errors, in many cases, the therapy is better when we attempt to
monitor the patients plasma concentration to optimize therapy than if we dont.
This is called therapeutic monitoring. If done properly, the plasma concentrations
are rapidly attained and maintained within the therapeutic range throughout the
course of therapy. This is not to say all drugs should be monitored. Some drugs
have a such a wide therapeutic range or little to no toxic effects that the concentra-
tions matter very little. Therapeutic monitoring is useful when:
a correlation exists between response and concentration,
the drug has a narrow therapeutic range,
the pharmacological response is not easily assessed, and
there is a wide inter-subject range in plasma concentrations for a given dose.
In this era of DRGs, where reimbursement is no longer tied to cost, therapeutic
monitoring of key drugs can be economically beneficial to an institution. A recent
study (DeStache 1990) showed a significant difference with regard to length of
stay in the hospital between the patients on gentamicin who were monitored (and
their dosage regulated as a consequence) vs. those who were not. With DRGs the
hospital was reimbursed a flat fee irrespective of the number of days the patient
stayed in the hospital. If the number of days cost less than what the DRG paid, the
hospital makes money. If the days cost more than the hospital loses money. This
study showed that if all patients in the hospital who were on gentamicin were mon-
itored, the hospital would save $4,000,000. Thats right FOUR MILLION per year.
I would say that would pay my salary, with a little left over, and that is only one
drug!
The process of
therapeutic monitoring
takes effort.
First the MD must order the blood assays.
Second, someone (nurse, med tech, you) must take the blood.
Someone (lab tech, you) must assay the drug concentration in the blood.
You must interpret the data.
You must communicate your interpretation and your recommendations for dosage regimen
change to the MD. This will allow for informed dosage decisions.
You must follow through to ensure proper changes have been made.
You must continue the process throughout therapy. Therapeutic drug monitoring, in many cases,
will be part of your practice. It can be very rewarding.
Thus, if we have determined the therapeutic range, we could use pharmacokinetics
to determine the optimum dosage regimen to maintain the patients plasma con-
centration within that range.
Selected References
1. Nagashima, R., OReilly, RA., and Levy, G, Kinetics of pharmacologic effects in man: the anticoagulant action of warfarin. Clin.
Pharm. Therap, 10 22-35 (1969).
2. Wagner, J.G, Relations between drug concentration and response. J. Mond. Pharm., 4, 279-310 (1971).
3. Gibaldi M. and Levy, G. Dose-dependent decline of pharmacologic effects of drugs with linear pharmacokinetics characteris-
tics. J.Pharm.Sci, 61, 567-569 (1972).
4. Brunner, L., Imhof, P., and Jack, D. Relation between plasma concentrations and cardiovascular effects of oral oxprenolol in
man. Europ. J. Clin. Pharmacol., 8, 3-9 (1975).
5. Galeazzi, R.L., Benet, L.Z., and Sheiner, L.B. Relationship between the pharmacokinetics and pharmacodynamics of procaina-
mide. Clin. Pharm. Therap., 20, 67-681 (1976).
6. Joubert, P., et al. Correlation between electrocardiographic changes, serum digoxin, and total body digoxin content. Clin.
Pharm. Therap., 20, 676-681 (1976).
7. Amery, A., et al. Relationship between blood level of atenolol and pharmacologic effect. Clin. Pharm. Therap., 21, 691-699
(1977).
3.4 Problems
What to do.---> We want to get pharmacokinetic data (elimination rate con-
stant) from pharmacological response data (Response vs concontration and
Response vs time graphs) .
Response vs Time Graph
1. Plot Response vs Time on Cartesian (regular) Graph Paper.
2. Use Response data between 20 and 80 percent of maximum (Pick the straight part) to do the lin-
ear regression on. (Rule of thumb: Connect first and last data point with a straight line. If all
the points fall on one side of the line, its not straight!
3. Find the slope of the straight line, , (eyeball the rise over the run or use linear regression as
required). Important: you must determine the best fit line through all of the points that you will
use. Eyeball method: Get the line as close to the points as possible placing as many points
above the line as below the line. Take two points on the line (not data points) to calculate the
change in Y over the change in X.
Response vs Ln(Concentration) Graph
1. Turn semi-log paper on its side so that the numbers are on the top.
What we are attempting to do is get the logarithm part of the paper on the x axis and have the
numbers get bigger as you go from left to right.
2. Plot concentration on the x axis and response on the y.
3. Find the slope of the line plotted this way by the rise over the run method.
Run is change in ln(C).
If you take any two concentrations such that C2 = 2*C1 then the run is (ln(C2) - ln(C1)).
Using rules of logs, when two logs are subtracted, the numbers are devided, thus: = ln(C2/C1).
If C2 = 2*C1 then ln(C2/C1) = ln(2) = 0.693.
0.0
0.2
0.4
0.6
0.8
1.0

10 10 10 10 10 10
R
e
s
p
o
n
s
e
Time
dR
dT
-------
10
-8
10
-7
10
-6
10
-5
10
-4
10
-3
10
-2
10
-1
Conc.
0.0
0.2
0.4
0.6
0.8
1.0
R
e
s
p
o
n
s
e

1
10
10
10

0
1
10
100
1
1
0
1
0
1
0

0
1
0
0
1 1
0
Concentration
R
e
s
p
o
n
s
e
Rise = change in Response.
Take the difference of the two responses coresponding to the concentrations picked. (R2-R1).
4. The slope of the line is
Ln(Concentration) vs Time Graph (Pharmacokinetic Data)
If you have concentration vs Time data:
1. Plot Concentration vs time on semi-log paper (Y axis is concentration this time)
2. Find the slope as before, using semi log paper (Remeber the log is on the Y axis this time, so you
find two concentrations such that c2 = 2*c1 and put it in the rise this time. Thus the slop of the
line is
If you have pharmacological response data:
1. Divide the slope of the Response vs Time graph by the slope of the Response vs ln(C) graph:
Both methods should be equivalent.
Additional problems are available in chapter 14, practice exams.
m
rise
run
--------
R
2
R
1
0.693
------------------ = =
1
10
10
10

0
C
o
n
c
e
n
t
r
a
t
i
o
n
Time
1
10
100
m
rise
run
--------
0.693
t
2
t
1
--------------
0.693
t
1
2
---
------------- k = = = =
slope of r vs t
slope of r vs ln(c)
------------------------------------------
dR
dT
-------
dR
dln(C)
---------------
---------------
dln(C)
dT
--------------- m k = = = =
Oxpranolol (Problem 0 - 1)
Brunner et al, Europ. J. Clin. Pharmacol., 8, 3-9 (1975).
In humans, the pharmacological response to oxpranolol (a beta blocker) is a decrease in beats per minute (bpm) com-
pared to placebo during physical exercise. The following approximate mean data is from 7 healthy volunteers: beats per
minute (bpm) altered with time (t) after oral administration of three doses (D).
1. Calculate the half life of oxpranolol from the pharmacological response table.
2. Plot plasma concentration data on Cartesian graph paper directly as well as transforming into .
3. Plot plasma concentration data on semilog paper. Use linear regression to find the rate constant of elimination of
oxpranolol.
4. Calculate the half life obtained from the concentration data and compare it with the half life calculation based on the
pharmacological response.
Problem Submitted By: Maya Leicht AHFS 00:00.00
Problem Reviewed By: Vicki Long GPI: 0000000000
TABLE 2-19
Response vs
Concentration
Response vs
time
BPM Dose (mg) BPM Time (hr)
10 40 17.6 1
13.5 60 13.9 2
16 80 10.2 3
19 120 6.6 4
21 160
TABLE 2-20 Oxpranolol plasma concentration following 160 mg IV dose
Time (min)

30 699
60 622
120 413
150 292
240 152
360 60
480 24
C
p
ng
ml
------
,
_
t
1 2
( )
C
p
C
p
ln
Minoxidil (Problem 0 - 2)
Shen et al. Clin. Pcol. Ther 17:593-8 (1975)
Minoxidil is a potent antihypertensive which lowers the mean arterial blood pressure (MAP) in certain patients.
From the preceding information, determine the following:
1. Graph and find (slope of (R)esponse vs. ln(C)oncentration graph).
2. Graph and find (slope of (R)esponse vs. (T)ime graph).
3. Find the ln(C)oncentration vs. (T)ime slope : : Note that your slope . If you are having problems
understanding this, refer to Sections 2.4.2 -2.4.4. K is the elimination rate constant.
PROBLEM TABLE 0 - 2. Minoxidil
Initial decrease in MAP Dose
17 2.5
40 5.0
53 7.5
63 10.0
76 15
PROBLEM TABLE 0 - 2. Minoxidil
25 mg I.V. Bolus yielded:
Decrease in MAP Time
75 20
66 30
56 40
48 50
mmHg ( ) mg ( )
mmHg ( ) hr ( )
dR
d C ln
------------
dR
dt
-------
dR
dt
-------
dR
d C ln
------------
------------- m K =
4. Calculate . t
1 2
0.693
K
-------------
,
_
=
Propranolol (Problem 0 - 3)
Citation?
Beta blockers can be considered first line drugs of choice in the treatment of hypertension in certain patients. The fol-
lowing data was obtained regarding Propranolol used to treat hypertension in a group of patients.
From the preceding information, determine the following:
3. Find the ln(C)oncentration vs. (T)ime slope : : Note that your slope . If you are having problems
understanding this, refer to Sections 2.4.2 -2.4.4.
PROBLEM TABLE 0 - 3. Propranolol
Fall in Systolic BP (mmHg)
20 50
16 40
11 30
5 20
PROBLEM TABLE 0 - 3. Propranolol
I.V. Bolus dose of Propranolol
Fall in Systolic BP (mmHg) Time (hr)
24 1
20 2
19 3
9 6
C
p
dR
d C ln
------------
dR
dt
-------
dR
dt
-------
dR
d C ln
------------
------------- m K =
4. Calculate . t
1 2
0.693
K
-------------
,
_
=
3.4.1 ANSWERS: OXPRANOLOL
1. Calculate the half life of oxpranolol from the pharmacological response table
Slope of the line from linear regression. Chapter 2.4.4
TABLE 3.
X
ln(Dose) Dose
Y
Response
3.689 40 10 13.61 36.89
4.094 60 13.5 16.76 55.27
4.382 80 16 19.20 70.11
4.787 120 19 22.92 90.96
5.075 160 21 25.75 106.58
t
1 2
( )
10 10 10
Dose (mg)
10
12
14
16
18
20
22

Oxpranolol
R
e
s
p
o
n
s
e

(
B
P
M
)
1 2
3
X
2
X Y
X 22.03 = Y 79.5 =
X
2
98.25 =
XY 359.82 =
X ( )
2
485.23 =
X
X
n
--------- 4.41 = =
)
y
y
n
------ 15.9 = =
)
m
x ( ) y ( ) ( ) n x y ( ) ( )
x ( ) [ ]
2
n x
2
( ) ( )
--------------------------------------------------------------------- =
m
22.03 79.5 ( ) 5 359.82 ( )
485.32 5 98.25 ( )
-------------------------------------------------------------------- 7.93 = =
the slope is equal to the linear regression of the change in response vs. ln concentration.
The slope of this plot is therefore, .
half life (89 min).
2. Plot plasma concentration data on Cartesian graph paper directly as well as transforming into .
dR
d c ln
----------- 7.93 =
1.5 2.0 2.5 3.0 3.5 4.0
6
8
10
12
14
16
18
OXPRANOLOL

Time (hr)
1.0
R
e
s
p
o
n
s
e

(
B
P
M
)
m
R
1
R
2
T
1
T
2
------------------
16 10
1.45 3.07
--------------------------- 3.71 = = =
dR
dt
------- 3.71 =
dR
dt
-------
dR
d c ln
-----------
-----------
d c ln
dt
----------- k
3.71
7.93
------------- 0.4678hr
1
= = = = t
1 2
2 ln
k
--------
0.693
0.4678hr
1
--------------------------- 1.48hr = = =
C
p
C
p
ln
3. Plot plasma concentration data on semilog paper. Use linear regression to find the rate constant of elimination of
oxpranolol.
Using linear regression, as described above, the elimination rate constant is approximately
0.007797 min
-1
* (60 min/hr) = 0.4678 hr
-1

4. Calculate the half life obtained from the concentration data and compare it with the half life calculation based on the
pharmacological response.
compared to 1.48 hours (89 min) from the pharmacological response
method.
0 100 200 300 400 500
Time (min)
Plasma concentration vs. Time
C
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
l
)

0
160
320
480
640
800
0 100 200 300 400 500
Time (min)
10
10
10

Oxpranolol
C
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
L
)
1
2
3
t
1 2
0.693
0.00763
------------------- 90min 1.5 hrs = = =
3.4.2 ANSWERS: MINOXIDIL
NOTE: Answers will vary depending on whether linear regression is calculated
via calculator or using the formula such as observed in Problem 1. Either method
can be used. However, if you use the formula, you should be within 10% of the
calculated answer. A word of caution: if you choose to do linear regression via
calculator make sure you have valid data. This cannot be assured until you have
graphed all the data points given. Many a student has incorrectly calculated
parameters because he/she falsely assumes that all the points are valid. Blindly
choosing data points for linear regression will only lead to error. Every problem
in this manual has been derived from actual journal articles and will therefore be
real data. This real-world data is inexact.

10 10 10
0
20
40
60
80
m
H
g
)

R vs Ln(C)
Dose (mg)
dR
d C ln
------------
dR
d C ln
------------ 32.96 =
dR
dt
-------

3. Find the ln(C)oncentration vs. (T)ime slope : : Note that your slope .

4. Calculate .

20 25 30 35 40 45 50
Time (hr)
45
50
55
60
65
70
75
m
m
H
R vs T
dR
dt
------- 0.91 =
dR
dt
-------
dR
d C ln
------------
------------- m K =
K 0.028hr
1
=
0.91
32.96
------------- 0.028 ( ) =
t
1 2
0.693
K
-------------
,
_
=
t
1 2
0.693
0.028hr
1
------------------------
,
_
24.75hr = =
3.4.3 ANSWERS: PROPRANOLOL


dR
d C ln
------------
10 10
0
5
10
15
20
R vs T
dR
d C ln
------------ 16.36 =
dR
dt
-------
0 1 2 3 4 5 6
5
10
15
20
25
R vs T
dR
dt
------- 2.93 =
3. Find the ln(C)oncentration vs. (T)ime slope : : Note that your slope .

4. Calculate .

dR
dt
-------
dR
d C ln
------------
------------- m K =
K 0.179hr
1
=
2.93
16.36
------------- 0.179 =
t
1 2
0.693
K
-------------
,
_
=
t
1 2
0.693
0.179hr
1
------------------------
,
_
3.87hr = =
CHAPTER 4 I.V. Bolus Dosing
OBJECTIVES
For an IV one compartment model plasma and urine:
1. Given patient drug and/or metabolite concentration, amount, and/or rate vs. time
profiles, the student will calculate (III) the relevant pharmacokinetic parameters
available from IV plasma, urine or other excreta data: e.g.
2. The student will provide professional communication regarding the pharmacoki-
netic parameters obtained to patients and other health professionals.
3. The student will be able to utilize computer programs for simulations and data
analysis.
V
d
K k
m
k
r
AUC AUMC CL MRT t
1 2
, , , , , , , ,
I.V. Bolus Dosing
4.1 I.V. Bolus dosing of Parent compound
4.1.1 PLASMA
Valid equations:
(Obtained from the
LaPlace transforms
derived from the
appropriate models
derived from the
pharmacokinetic
descriptions of the drug)
(EQ 4-1)
(EQ 4-2)
(EQ 4-3)
(EQ 4-4)
(EQ 4-5)
(EQ 4-6)
(EQ 4-7)
(EQ 4-8)
(EQ 4-9)
Utilization:
Can you determine the
slope and intercept from
a graph? Plot the data
in table 4 -1.on semi-log
graph paper. Extrapo-
late the line back to time
= 0 to get Cp
0
. Find the
half life. Calculate the
elimination rate con-
stant.
You should be able to plot a data set Concentration vs. time on semilog yielding a straight line
with slope = and an intercept of .
FIGURE 4-1.
C
p
ln K1 t C
p
0
ln + =
X ln K1 t X
0
ln + =
C
p
C
p0
e
K1t
=
C
p
0
D
V
d
------ =
t
0.693
K
------------- =
AUC Cp t d
0
( )
=
Cp
n
Cp
n 1 +
+ ( )
2
------------------------------------- t
,
_
Cp
last
K1
-------------- + =
AUMC t C p t d
t
n
Cp
n
( ) t
n 1 +
Cp
n 1 +
( ) +
2
-------------------------------------------------------------------- t
,
_
0
t
Cp
last
K1
2
---------------
t
last
Cp
last
( )
K1
---------------------------------- + + =
0
( )
=
MRT
AUMC
AUC
------------------ =
Cl K V
d
=
TABLE 4-1. Nifedipine 25 mg IV bolus
Time (hr)
Cp
(mcg/L)
2 139
4 65.6
6 31.1
8 14.6
K1
C
p0
I.V. Bolus Dosing
Does your Graph look
like this?
FIGURE 4-1. Nifedipine IV Bolus (25 mg IV Bolus)
You should be able to determine K1. A plot of the data in TABLE 4-1. results in FIGURE 4-
1. Remember from high school algebra, the slope of any straight line is the rise over the run,
, In the case of semi-log graphs dy is the difference in the logarithms of the concentrations.
Thus, using the rules of logarithms, when two logs are subtracted, the numbers themselves are
divided. i.e. . Thus if we are judicious in the concentrations that we
take, we can set the rise to a constant number. So, if we take any two concentrations such that
one concentration is half of the other (In FIGURE 4-1. above, we took 100 and 50), the time it
takes for the concentration to halve is the half life (in the graph above, 1.85 hr). Then
You should be able to determine :. To do this, extrapolate the line to . The value of
when is (in the graph above, which is equal to for an IV bolus
dose only.
Thus,
The volume of distribution is a mathematical construct. It is merely the proportionality constant
between two knowns - the which results from a given . It is, however, useful because it
is patient specific and therefore can be used to predict how the patient will treat a subsequent
dose of the same drug. You should be able to obtain the volume of distribution from graphical
analysis of the data. Pay attention to the units! Make sure that they are consistent on both sides
of the equation. NOTE: the volume of distribution is not necessarily any physiological space.
For example the approximate volume of distribution of digoxin is about 600 L If that were a
physiological space and I were all water, that would mean that I would weigh about 1320
pounds. I'm a little overweight (I prefer to think that I'm underheight), but REALLY!
Given any three of the variables of the IV bolus equation, either by direct information (the vol-
ume of distribution is such and such) or by graphical data analysis, you should be able to find
the fourth.
You should be able to calculate Area Under the Curve (AUC) from IV Bolus data (Time vs. Cp).
From the above data in TABLE 4-1. the AUC is calculated using (EQ 4-6):
0 2 4 6 8
Time (hours)
101
102
103
C
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
L
)

-K1 = -0.375 hr
-1
C
p0
= 295 mic/L

C
o
n
c
e
n
t
r
a
t
i
o
n

(
m
i
c
/
L
)
Time (hr)
1.85 hr
100
50
dy
dx
------
C1 ( ) ln C2 ( ) ln
C1
C2
-------
,
_
ln =
K1
0.693
t
-------------
0.693
1.85hr
---------------- 0.375 hr
1
= = =
V
d
t 0 = C
p
t 0 = C
p0
C
p0
295
mic
L
--------- = D V
d
Cp
0
Dose
V
d
------------- V
d
Dose
Cp
0
-------------
25mg
295mic
L
------------------
------------------ =
1000mic
mg
--------------------- 85L = = , =
C
p0
D
0
I.V. Bolus Dosing
which in this case is:
or
. In tabular format, the AUC calculation
is shown in TABLE 4-2.
The AUC of a plot of plasma concentration vs. time, in linear pharmacokinetics, is a number
which is proportional to the dose of the drug which gets into systemic circulation. The propor-
tionality constant, as before, is the volume of distribution. It is useful as a tool to compare the
amount of drug obtained by the body from different routes of administration or from the same
route of administration by dosage forms made by different manufacturers (calculate bioavail-
ability in subsequent discussions).
The AUC of a plot of Rate of Excretion of a drug vs. time, in linear pharmacokinetics, is the
mass of drug excreted into the urine, directly.
You should be able to calculate the AUMC from IV Bolus data (Time vs. Cp). The equation for
AUMC is equation 4-7:
which in the
data given in TABLE 4-1. is:
+
and thus,
TABLE 4-2 AUC
TIME Cp
0 295
2 139 434.0 434.0
4 65.6 204.6 638.6
6 31.1 96.7 735.3
8 14.6 45.7 781.0
0 38.9 819.9
AUC Cp t d
0
( )
=
Cp
n
Cp
n 1 +
+
t
---------------------------------
,
_
Cp
l
K1
-------- + =
Cp
o
Cp
1
+
2
-------------------------- t
1
Cp
1
Cp
2
+
2
-------------------------- t
2
Cp
2
Cp
3
+
2
-------------------------- t
3
Cp
3
Cp
last
+
2
------------------------------- t
last
Cp
last
K1
--------------- + + + +

' ;

295 139 +
2
------------------------ 2
139 65.6 +
2
------------------------- 2
65.6 31.1 +
2
--------------------------- 2
31.1 14.6 +
2
--------------------------- 2
14.6
0.375
------------- + + + +

' ;

mcg
L
----------hr
434 204.6 96.7 45.7 38.9 + + + + { }
mcg
L
----------hr 819.9
mcg
L
----------hr =
AUC
t 1
t
AUC
0
t
AUMC t C p t d
t
n
Cp
n
( ) t
n 1 +
Cp
n 1 +
( ) +
2
-------------------------------------------------------------------- t
,
_
0
t
Cp
last
K1
2
---------------
t
last
Cp
last
( )
K1
---------------------------------- + + =
0
( )
T
0
C p
o
T
1
C p
1
+
2
----------------------------------------------- t
1
T
1
C p
1
T
2
C p
2
+
2
----------------------------------------------- t
2
T
2
C p
2
T
3
C p
3
+
2
----------------------------------------------- t
3
+ +
T
3
C p
3
T
last
C p
last
+
2
---------------------------------------------------------- t
last
T
last
C p
last
K1
-------------------------------
Cp
last
K1
2
--------------- + +
I.V. Bolus Dosing
+
or
Thus in tabular format the AUMC for data given in TABLE 4-1. is TABLE 4-3 below.
The AUMC is the Area Under the first Moment Curve. A plot of T*Cp vs. T is the first
moment curve. The time function buried in this plot, the Mean Residence Time (MRT), can be
extracted using equation 4-8 below.
It is the geometric mean time that the molecules of drug stay in the body. It has utility in the fact
that, as drug moves from the dosage form into solution in the gut, from solution in the gut into
the body, and from the body out, each process is cumulatively additive. That means if we can
physically separate each of these processes in turn, we can calculate the MRT of each process.
The MRT of each process is the the inverse of the rate constant for that process.
You should be able to calculate MRT from IV Bolus data (Time vs. Cp) using equation 4-8
Since there is only the process of elimination (no release of the drug from the dosage form, no
absorption), the MRT is the inverse of the elimination rate constant, K. Thus MRT = 1/K.
Flow Chart 2-1 IV Bolus
TABLE 4-3 AUMC
TIME Cp Cp*T
0 295 0
2 139 278 278.0 278.0
4 65.6 262.4 540.4 818.4
6 31.1 186.6 449.0 1267.4
8 14.6 116.8 303.4 1570.8
0 0 415.3 1986.1
0 295 2 139 +
2
--------------------------------------- 2
2 139 4 65.6 +
2
---------------------------------------- 2
4 65.6 6 31.1 +
2
------------------------------------------ 2 + +

' ;

mcg
L
----------hr
2
6 31.1 8 14.6 +
2
------------------------------------------ 2
8 14.6
0.375
------------------
14.6
0.375
2
---------------- + +

' ;

mcg
L
----------hr
2
278 540.4 449 303.4 311.47 103.82 + + + + + { } 1986.1
mcg
L
----------hr
2
=
AUMC
t
AUMC
0
t
MRT
AUMC
AUC
------------------ =
1986.1
819.9
---------------- 2.42 = =
X
K
MRT(IV) = 1/K
I.V. Bolus Dosing
Suppose the drug were given in a solution. Then the drug would have to be absorbed and then
eliminated. Since the MRTs are additive, the MRT of the oral solution would be made up of the
MRTs of the two processes, thus:
Flow Chart 2-2 Oral Solution
Consequently, if a drug has to be released from a dosage form for the drug to get into solution
which is subsequently absorbed, a tablet for example, the MRT of the tablet will consist of the
MRT(IV) and the MAT(os) and the Mean Dissolution Time (MDT), thus:
Flow Chart 2-3 Tablet
Normally, we dont have information from the oral solution, just IV and tablet. So in that case
the information obtained about absorption from the tablet is bundled together into an apparent
absorption rate constant consisting of both dissolution and absorption.
It should be apparent that this is a reasonably easily utilized and powerful tool used to obtain
pharmacokinetic parameters.
K Ka
X Xa
MRT(os) = MAT(os)+MRT(IV)
MRT(os) = 1/Ka + 1/K
X Xa Xd
Kd Ka K
MRT(tab) = MDT + MAT(os) + MRT(IV)
MRT(tab) = 1/Kd + 1/Ka + 1/K
MRT(tab) = MAT(tab) + MRT(IV)
MRT(tab) = 1/Ka (apparent) + 1/K
I.V. Bolus Dosing
4.1.2 IV BOLUS, PARENT COMPOUND, PLASMA PROBLEMS
Equations used in this
section:
1. from equation 4-3
2. equation 4-5
3. equation 4-8
4. = the y-intercept of the line from equation 4-3
5. Estimate for AUC = which is

Trapezoidal rule applied to equation 4-6
6. Estimate for AUMC = from equation 4-8

from equation 4-7
7. from equation 4-4
8.
K1 slope =
t
1 2
2 ln
K1
-------- =
MRT
1
K1
------- estimate ( ) = MRT
AUMC
AUC
------------------ =
Cp
0
AUC
Cp
0
K1
--------- = Cp t d
0
AUC Cp t d
0
( )
=
Cp
n
Cp
n 1 +
+ ( )
2
-------------------------------------
,
_
t ( )
Cp
last
K1
-------------- + =
AUMC AUC MRT =
AUMC Cp t d
t
n
Cp
n
( ) t
n 1 +
Cp
n 1 +
( ) +
2
-------------------------------------------------------------------- t
n
,
_
0
t
Cp
last
K1
2
---------------
t
last
Cp
last
( )
K1
---------------------------------- + + =
0
( )
V
d
Dose
Cp
0
------------- =
Cl K1 V
d
Cp
0
AUC
------------
Dose
Cp
0
------------- =
Dose
AUC
------------- = =
I.V. Bolus Dosing
Acyclovir (Problem 4 - 1)
De Miranda and Burnette, Metabolic Fate and Pharmacokinetics of the Acyclovir Prodrug Valaciclovir in Cynomolgus Mon-
keys, Drug Metabolism and Disposition (1994): 55-59.
Acyclovir is an antiviral drug used in the treatment of herpes simplex, varicella zoster, and in suppressive therapy. In
this study, three male cynomolgus monkeys were each given a 10 intravenous dose. The monkeys weighed an
average of 3.35 each. Blood samples were collected and the following data was obtained:
From the data presented in the Preceding table, determine the following:
1. Find the elimination rate constant, .
2. Find the half life, .
3. Find .
4. Find .
5. Find the Area Under the Curve, .
6. Find the area under the first moment curve, .
7. Find the volume of distribution,
8. Find the clearance, .
Problem Submitted By: Maya Leicht AHFS 12:34.56 Antivirals
Problem Reviewed By: Vicki Long GPI: 0000000000 Antivirals
PROBLEM TABLE 4 - 1. Acyclovir
Time (hours)
Serum concentration
0.167 26.0
0.300 23.0
0.500 19.0
0.75 16.0
1.0 12.0
1.5 7.0
2.0 5.0
mg kg
kg
g mL ( )
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 1) Acyclovir:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .

0.5 1.0 1.5 2.0
10
10
10
0.0
0
1
2
C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
I
C
/
M
L
)
TIME (HR)
k 0.93hr
1
=
t
0.75hr =
MRT 1.08hr =
C
p
( )
0
30.4ug mL =
AUC 32.75ug mL hr =
AUMC 35.2ug mL hr
2
=
V
d
1.1L =
Cl 1.02L hr =
I.V. Bolus Dosing
Aluminum (Problem 4 - 2)
Xu, Pai, and Melethil, "Kinetics of Aluminum in Rats. II: Dose-Dependent Urinary and Biliary Excretion", Journal of Pharmaceu-
tical Sciences, Oct 1991, p 946 - 951.
A study by Xu, Pai, and Melethil establishes the pharmacokinetics of Aluminum in Rats. In this study, four rats with an
average weight of 375g, were given an IV bolus dose of aluminum (1 mg/kg). Blood samples were taken at various
intervals and the following data was obtained:
From the data presented in the preceding table, determine the following:
3. Find .
4. Find .
PROBLEM TABLE 4 - 2. Aluminum
Time (hours)
Serum concentration,
0.4 19000
0.6 18000
1.4 15000
1.6 14500
2.3 12500
3.0 10500
4.0 8500
5.0 6500
6.0 5000
8.0 3250
10.0 2000
12.0 1250
ng
mL
--------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 2) Aluminum:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .

0 2 4 6 8 12
10
10
10
10
TIME (HR)
C
O
N
C
E
N
T
R
A
T
I
O
N

(
N
G
/
M
L
)
3
4
5
k 0.234hr
1
=
t
3hr =
MRT 4.3hr =
C
p
( )
0
21000ng mL =
AUC 89285ng mL hr =
AUMC 383926ng mL hr
2
=
V
d
17.86mL =
Cl 4.18mL hr =
I.V. Bolus Dosing
Amgen (Problem 4 - 3)
Salmonson, Danielson, and Wikstrom, "The pharmacokinetics of recombinant human erythropoetin after intravenous
and subcutaneous administration to healthy subjects", Br. F. clin. Pharmac. (1990), p 709- 713.
Amgen (r-Epo) is a form of recombinant erythropoetin. Erythropoetin is a hormone that is produced in the kidneys and
used in the production of red blood cells. The kidneys of patients who have end-stage renal failure cannot produce
erythropoetin; therefore, r-Epo is being investigated for use in these patients in order to treat the anemia that results
from the lack of erythropoetin. In a study by Salmonson et al, six healthy volunteers were used to demonstrate that
both IV and subcutaneous administration of erythropoetin have similar effects in the treatment of anemia due to
chronic renal failure. The six volunteers were each given a 50 U/kg intravenous dose of Amgen. The average weight
of the six volunteers was 79 kg. Blood samples were drawn at various times and the data obtained is summarized
below:
3. Find .
4. Find .
PROBLEM TABLE 4 - 3. Amgen
Time (hours)
2 700
4 600
6 400
8 300
12 150
24 40
mU
mL
---------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 3) Amgen:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 5 10 15 20 25
10
1
10
2
10
3
C
o
n

(
m
U
/
m
L
)

TIME (HR)
C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
U
/
M
L
)
k 0.134hr
1
=
t
5.2hr =
MRT 7.46hr =
C
p
( )
0
900mU mL =
AUC 6945mU mL hr =
AUMC 49600 = mU mL hr
2

V
d
4.44L =
Cl 0.6L hr =
I.V. Bolus Dosing
Atrial Naturetic Peptide (ANP) (Problem 4 - 4)
Brier and Harding, "Pharmacokinetics and Pharmacodynamics of Atrial Naturetic Peptide after Bolus and Infusion Administra-
tion in the Isolated Perfused Rat Kidney", The Journal of Pharmacology and Experimental Therapeutics (1989), p 372 - 377.
A study by Brier and Harding a dose of 45 ng was given by IV bolus to rats. Samples of blood were taken at various
intervals throughout the length of the study and the following data was obtained:
3. Find .
4. Find .
PROBLEM TABLE 4 - 4. Atrial Naturetic Peptide (ANP)
Time (minutes)
3 380
10 280
20 170
30 130
40 100
50 70
60 50
pg
mL
--------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 4) Atrial Naturetic Peptide (ANP):
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 10 20 30 40 50 60
Time (min)
10
1
10
2
10
3
C
o
n

(
p
g
/
m
L
)

ANP
C
O
N
C
E
N
T
R
A
T
I
O
N

(
P
G
/
M
L
)
k 0.0345min
1
=
t
20.09min =
MRT 28.95min =
C
p
( )
0
386.6pg mL =
AUC 11206.4pg mL min =
AUMC 324425.4pg mL min
2
=
V
d
116.4mL =
Cl 4.02mL min =
I.V. Bolus Dosing
Aztreonam (Problem 4 - 5)
Cuzzolim et al., "Pharmacokinetics and Renal Tolerance of Aztreonam in Premature Infants", Antimicrobial Agents and Chemo-
therapy (Sept. 1991), p. 1726 - 1928.
Aztreonam is a monolactam structure which is active against aerobic, gram-negative bacilli. The pharmacokinetic
parameters of Aztreonam were established in a study presented in by Cuzzolim et al in which Aztreonam (100 mg/ kg)
was administered intravenously to 30 premature infants over 3 minutes every 12 hours. The group of neonates had an
average weight of 1639.6g. The following set of data was obtained:
3. Find .
4. Find .
PROBLEM TABLE 4 - 5. Aztreonam
Time (minutes)
1 40.50
2 34.99
3 29.99
4 23.88
5 22.20
6 19.44
7 16.55
8 14.99
g
mL
--------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 5) Aztreonam:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 2 4 6 8
10
1
10
2
C
o
n

(
u
g
/
m
L
)

Aztreonam
TIME (MIN)
C
O
N
C
E
N
T
R
A
T
I
O
N

(
U
G
/
M
L
)
k 0.144min
1
=
t
4.81min =
MRT 6.94min =
C
p
( )
0
45.75ug mL =
AUC 317.7ug mL min =
AUMC 2204.8ug mL min
2
=
V
d
3.58L =
Cl 0.516L min =
I.V. Bolus Dosing
Recombinant Bovine Placental Lactogen (Problem 4 - 6)
Byatt, et. al., "Serum half-life and in-vivo actions of recombinant bovine placental lactogen in the dairy cow", Journal of Endocri-
nology (1992), p. 185 - 193.
Bovine placental lactogen (bPL) is a hormone similar to growth hormone and prolactin. It binds to both prolactin and
growth hormone receptors in the rabbit and stimulates lactogenesis in the rabbit. In a study by Byatt, et. al., four cows
(2 pregnant and 2 nonpregnant) were given IV bolus injections of 4 mg and the following data was obtained:
3. Find .
4. Find .
PROBLEM TABLE 4 - 6. Recombinant Bovine Placental Lactogen
Time (minutes)
Serum concentration
3.8 117
6.8 72
12.0 43
16.0 27
20.0 18
g
L
------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 6) Recombinant Bovine Placental Lactogen:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 5 10 15 20
Time (min)
10
1
10
2
10
3
C
o
n

(
u
g
/
L
)

C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
I
C
/
L
)
k 0.113min
1
=
t
6.13min =
MRT 8.85min =
C
p
( )
0
167.8ug L =
AUC 1484.9ug L min =
AUMC 13141.1ug L min
2
=
V
d
23.84L =
Cl 2.69L min =
I.V. Bolus Dosing
Caffeine (Problem 4 - 7)
Dorrbecker et. al., "Caffeine and Paraxanthine Pharmacokinetics in the Rabbit: Concentration and Product Inhibition Effects.",
Journal of Pharmacokinetics and Biopharmaceutics (1987), p.117 - 131.
This study examines the pharmacokinetics of caffeine in the rabbit. In this study type I New Zealand White rabbits
were given an 8 mg intravenous dose of caffeine. Blood samples were taken and the following data was obtained:
3. Find .
4. Find .
PROBLEM TABLE 4 - 7. Caffeine
Time (minutes)
Serum concentration
12 3.75
40 2.80
65 2.12
90 1.55
125 1.23
173 0.72
243 0.37
g
mL
--------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 7) Caffeine:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 50 100 150 200 250
Time (min)
10
-1
10
0
10
1
C
o
n

(
u
g
/
L
)

C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
I
C
/
M
L
)
k 0.00997min
1
=
t
69.51min =
MRT 100.3min =
C
p
( )
0
4.105ug mL =
2
=
V
d
1.95L =
Cl 19.44mL min =
I.V. Bolus Dosing
Ceftazidime (Problem 4 - 8)
Demotes-Mainard, et. al., "Pharmacokinetics of Intravenous and Intraperitoneal Ceftazidime in Chronic Ambulatory Peritoneal
Dyialysis", Journal of Clinical Pharmacology (1993), p. 475 - 479.
Ceftazidime is a third generation cephalosporin which is administered parenterally. In this study, eight patients with
chronic renal failure were each given 1 g of ceftazidime intravenously. Both blood samples were taken the data
obtained from the study is summarized in the following table:
3. Find .
4. Find .
PROBLEM TABLE 4 - 8. Ceftazidime
Time (hours)
Serum concentration
1 50
2 45
4 38
24 21
36 14
48 11
60 8
72 4
mg
L
-------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 8) Ceftazidime:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 20 40 60 80
Time (hours)
10
0
10
1
10
2
C
o
n

(
m
g
/
L
)

C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
G
/
L
)
k 0.0324hr
1
=
t
21.39hr =
MRT 30.86hr =
C
p
( )
0
47.57mg L =
AUC 1468.2mg L hr =
AUMC 45308.6mg L hr
2
=
V
d
21.02L =
Cl 0.681L hr =
I.V. Bolus Dosing
Ciprofloxacin (Problem 4 - 9)
Lettieri, et. al., "Pharmacokinetic Profiles of Ciprofloxacin after Single Intravenous and Oral Doses", Antimicrobial Agents and
Chemotherapy (May 1992), p. 993 -996.
Ciprofloxacin is a fluoroquinolone antibiotic which is used in the treatment of infections of the urinary tract, lower res-
piratory tract, skin, bone, and joint. In this study, twelve healthy, male volunteers were each given 300 mg intravenous
doses of Ciprofloxacin. Blood and urine samples were collected at various times throughout the day and the following
data was collected:
3. Find .
4. Find .
PROBLEM TABLE 4 - 9. Ciprofloxacin
Time (hours)
Serum concentration
2 1.20
3 0.85
4 0.70
6 0.50
8 0.35
10 0.25
mg
L
-------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 9) Ciprofloxacin:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 2 4 6 8 10
Time (hours)
10
-1
10
0
10
1
C
o
n

(
m
g
/
L
)

C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
G
/
L
)
k 0.1875hr
1
=
t
3.7hr =
MRT 5.33hr =
C
p
( )
0
1.57mg L =
AUC 8.395mg L hr =
AUMC 44.74mg L hr
2
=
V
d
190.6L =
Cl 35.74L hr =
I.V. Bolus Dosing
The effect of Probenecid on Diprophylline (DPP) (Problem 4 - 10)
Nadai et al, "Pharmacokinetics and the Effect of Probenecid on the Renal Excretion Mechanism of Diprophylline", Journal of
Pharmaceutical Sciences (Oct 1992), p. 1024 - 1027.
Diprophylline is used as a bronchodilator. A study by Nadai et al was designed to determine whether or not coadmin-
istration of Diprophylline with Probenecid affected the pharmacokinetic parameters of Diprophylline. In this study,
male rats (average weight: 300 g) were given 60 mg/kg of Diprophylline intravenously and a 3 mg/kg loading dose of
Probenecid followed by a continuous infusion of 0.217 mg/min/kg of Probenecid. The following set of data was
obtained for Diprophylline (DPP):
3. Find .
4. Find .
PROBLEM TABLE 4 - 10. The effect of Probenecid on Diprophylline (DPP)
Time (minutes)
Serum concentration
16 40.00
31 27.00
60 13.00
91 6.50
122 3.50
g
mL
--------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 10) The effect of probenecid on diprophylline (DPP):
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 20 40 60 80 100
Time (min)
10
0
10
1
10
2
C
o
n

(
u
g
/
m
L
)

C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
I
C
/
M
L
)
k 0.023min
1
=
t
30.13min =
MRT 43.48min =
C
p
( )
0
55.13ug mL =
2
=
V
d
326.5mL =
Cl 7.5mL min =
I.V. Bolus Dosing
Epoetin (Problem 4 - 11)
MacDougall et. al., "Clinical Pharmacokinetics of Epoetin (Recombinant Human Erythropoetin", Clinical Pharmacokinetics
(1991), p 99 - 110.
Epoetin is recombinant human erythropoetin. Erythropoetin is a hormone that is produced in the kidneys and used in
the production of red blood cells. The kidneys of patients who have end-stage renal failure cannot produce erythropo-
etin; therefore, Epoetin is used in these patients to treat the anemia that results from the lack of erythropoetin. Epoetin
has also been used in the treatment of anemias resulting from AIDS. malignant disease, prematurity, rheumatoid arthri-
tis, sickle-cell anemia, and myelosplastic syndrome. In a study by Macdougall et al, eight patients who were on perito-
neal dialysis (CAPD) were given an IV bolus dose of 120 U/kg which decayed monoexponentially from a peak of 3959
U/L to 558 U/L at 24 hours. The following data was obtained:
From the data presented in the preceding table and assuming that the patient weighs 65 kg, determine the following:
3. Find .
4. Find .
PROBLEM TABLE 4 - 11. Epoetin
Time (hours)
Serum concentration
0.0 4000
0.5 3800
1.0 3600
2.0 3300
3.0 3000
4.0 2550
5.0 2350
6.0 2150
7.0 1900
U
L
----
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 11) Epoetin:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 1 2 3 4 5 6 7
Time (hours)
10
3
10
4
C
o
n

(
U
/
L
)

C
O
N
C
E
N
T
R
A
T
I
O
N

(
U
/
L
)
k 0.107 hr
1
=
t
6.5 hr =
MRT 9.38 hr =
C
p
( )
0
4023 Units/L =
AUC 37775
Units hr
L
------------------------ =
AUMC 354697
Units hr
2
L
--------------------------- =
V
d
1.9 L =
Cl 0.2065
L
hr
----- =
I.V. Bolus Dosing
Famotidine (Problem 4 - 12)
Kraus, et. al., "Famotidine--Pharmacokinetic Properties and Suppression of Acid Secretion in Pediatric Patients Following Car-
diac Surgery", Clinical Pharmacokinetics (1990), p 77 - 80.
Famotidine is a histamine H2-receptor antagonist. The study by Kraus, et. al., focuses on the kinetics of famotidine in
children. In the study, ten children with normal kidney function and a body weight ranging from 14 - 25 kg, were each
given a single intravenous 0.3 mg/kg dose of famotidine. Blood and urine samples were taken providing the following
data:
From the data presented in the preceding table, determine the following assuming that the patient weighs 17.2 kg:
3. Find .
4. Find .
PROBLEM TABLE 4 - 12. Famotidine
Time (hours)
Serum concentration
0.33 300
0.50 250
1.00 225
4.00 125
8.00 70
12.00 40
16.00 15
g
L
------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 12) Famotidine:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 5 10 15 20
Time (hours)
10
1
10
2
10
3
C
o
n

(
u
g
/
m
L
)

C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
I
C
/
L
)
k 0.17 hr
1
=
t
3.9 hr =
MRT 5.7 hr =
C
p
( )
0
285
g
L
------ =
AUC 1600
g hr
L
----------------- =
AUMC 9000
g hr
2
L
------------------ =
V
d
18 L =
Cl 3.2L =
I.V. Bolus Dosing
Ganciclovir (Problem 4 - 13)
Trang, et. al., "Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections", Clin-
ical Pharmacology and Therapeutics (1993), p. 15 - 21.
Ganciclovir (mw: 255.23) is used against the human herpes viruses, cytomegalovirus retinitis, and cytomegalovirus
infections of the gastrointestinal tract. In this study, twenty-seven newborns with cytomegalovirus disease were given
4 mg/kg of ganciclovir intravenously over one hour. Blood samples were taken and the data obtained is summarized in
the following table:
From the data presented in the preceding table and assuming the patient weighs 3.6 kg, determine the following :
3. Find .
4. Find .
PROBLEM TABLE 4 - 13. Ganciclovir
Time (hours) Serum concentration
1.50 4.50
2.00 4.00
3.00 3.06
4.00 2.40
6.00 1.45
8.00 0.87
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 13) Ganciclovir:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .

0 2 4 6 8
10
10
10
C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
I
C
M
O
L
E
/
L
)
TIME (HR)
k 0.288hr
1
=
t
2.4hr =
MRT 3.5hr =
C
p
( )
0
23
mole
mL
---------------- =
AUC 80
mole hr
mL
-------------------------- =
AUMC 280
mole hr
2
mL
----------------------------- =
V
d
Dose
Cp
0
-------------
4
mg
kg
------- 3.6kg
1000 g
mg
-------------------
23
mole
L
---------------- 255.23
g
mole
----------------
------------------------------------------------------------- 2.45L = = =
Cl 0.7
L
hr
----- =
I.V. Bolus Dosing
Imipenem (Problem 4 - 14)
Heikkila, Renkonen, and Erkkola, "Pharmacokinetics and Transplacental Passage of Imipenem During Pregnancy", Antimicrobial
Agents and Chemotherapy (Dec. 1992), p 2652 - 2655.
Imipenem is a beta-lactam antibiotic which is used in combination with cilastin and is active against a broad spectrum
of bacteria. The pharmacokinetics of Imipenem in pregnant women is established in this study. Twenty women (six of
which were non-pregnant controls) were given a single intravenous dose of 500 mg of imipenem-cilastin (1:1). Blood
samples were taken at various intervals and the data obtained is summarized in the following table:
3. Find .
4. Find .
PROBLEM TABLE 4 - 14. Imipenem
Time (minutes)
Serum concentration
10 27.00
15 23.50
30 15.50
45 9.50
60 6.50
mg
L
-------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 14) Imipenem:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .

0 10 20 30 40 50 60
10
10
10
TIME (MIN)
C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
G
/
L
)
1
2
0
k 0.029 min
1
=
t
24 min =
MRT 34.5 min =
C
p
( )
0
36.2
mg
L
------- =
AUC 1250
mg min
L
--------------------- =
AUMC 43125
mg min
2
L
------------------------ =
V
d
Dose
Cp
0
-------------
500mg
36.2
mg
L
-------
------------------ 13.8L = = =
Cl 0.4
L
min
--------- =
I.V. Bolus Dosing
Methylprednisolone (Problem 4 - 15)
Patel, et. al., "Pharmacokinetics of High Dose Methylprednisolone and Use in Hematological Malignancies", Hematological
Oncology (1993), p. 89 - 96.
Methylprednisolone is a corticosteriod that has been used in combination chemotherapy for the treatment of hemato-
logical malignancy, myeloma, and acute lymphoblastic leukemia. In a study by Patel et. al., eight patients were given
1.5 gram intravenous doses of methylprednisolone from which the following data was obtained:
3. Find .
4. Find .
PROBLEM TABLE 4 - 15. Methylprednisolone
Time (hours)
Serum concentration
0.5 19.29
1.0 17.56
1.8 15.10
4.0 9.98
5.8 7.10
8.0 4.70
12.0 2.21
18.0 0.71
24.0 0.23
g
mL
--------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 15) Methylprednisolone:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 5 10 15 20 25
Time (hours)
10
-1
10
0
10
1
10
2
C
o
n

(
u
g
/
m
L
)

C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
I
C
/
M
L
)
k 0.188 hr
1
=
t
3.69hr =
MRT 5.3hr =
C
p
( )
0
21.2
g
mL
-------- =
AUC 112.5
g hr
mL
----------------- =
AUMC 598.4
g hr
2
mL
------------------ =
V
d
71L =
Cl 13.3
L
hr
----- =
I.V. Bolus Dosing
Omeprazole (Problem 4 - 16)
Anderson, et. al., "Pharmacokinetics of [14C] Omeprazole in Patients with Liver Cirrhosis", Clinical Pharmacokinetics (1993), p.
71 - 78.
Omeprazole (mw: 345.42) is a gastric proton-pump inhibitor which decreases gastric acid secretion. It is effective in
the treatment of ulcers and esophageal reflux. In normal patients 80% of the omeprazole dose is excreted as metabo-
lites in the urine and the remainder is excreted in the feces. In the study by Anderson, et. al., eight patients with liver
cirrhosis were given 20 mg, IV bolus doses of omeprazole. The patients had a mean body weight of 70 kg. Both blood
were taken at various intervals throughout the study and the following data was obtained:
From the data presented in the preceding table, determine the following :
3. Find .
4. Find .
PROBLEM TABLE 4 - 16. Omeprazole
Time (hours)
Serum concentration
0.75 3.49
1.00 3.25
2.00 2.46
3.00 1.86
4.00 1.40
5.00 1.06
6.00 0.80
7.00 0.61
8.00 0.46
10.00 0.26
12.00 0.15
mole
mL
----------------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 16) Omeprazole:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 2 4 6 8 10 12
Time (hours)
10
-1
10
0
10
1
C
o
n

(
u
m
o
l
/
m
L
)

Omeprazole
C
O
N
C
E
N
T
R
A
T
I
O
N

(
P
I
C
O
M
O
L
E
/
M
L
)
k 0.280hr
1
=
t
2.5hr =
MRT 3.57hr =
C
p
( )
0
4.3
mole
mL
---------------- =
AUC 15.4
mole hr
mL
-------------------------- =
AUMC 55
mole hr
2
mL
----------------------------- =
V
d
Dose
Cp
0
-------------
20mg
4.3
mole
mL
----------------
mmole
10
9
mole
-------------------------
345.42mg
mmole
------------------------
1000mL
L
--------------------
------------------------------------------------------------------------------------------------------------ 13465L = = =
Cl 3.9
L
hr
----- =
I.V. Bolus Dosing
Pentachlorophenol (Problem 4 - 17)
Reigner, Rigod, and Tozer, "Absorption, Bioavailability, and Serum Protein Binding of Pentachlorophenol in the B6C3F1 Mouse",
Pharmaceutical Research (1992), p 1053 - 1057.
Pentachlorophenol (PCP) is a general biocide. That is, it is an insecticide, fungicide, bactericide, herbicide, algaecide,
and molluskicide, that is used as a wood preservative. Extensive exposure to PCP can be fatal. In a study by Reigner
et al, six mice (average weight: 27 g) were given 15 mg/kg of PCP by intravenous bolus. Blood samples were taken at
various intervals from which the following data was obtained:
From the data presented in the preceding table, determine the following :
3. Find .
4. Find .
PROBLEM TABLE 4 - 17. Pentachlorophenol
Time (hours)
Serum concentration
0.083 38.00
4.000 22.00
8.000 14.00
12.000 7.90
24.000 1.30
28.000 0.75
32.000 0.60
36.000 0.40
g
mL
--------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 17) Pentachlorphenol:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 10 20 30 40
Time (hours)
10
-1
10
0
10
1
10
2
C
o
n

(
u
g
/
m
L
)

C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
I
C
/
M
L
)
k 0.134 hr
1
=
t
5.2hr =
MRT 7.5hr =
C
p
( )
0
35.6
g
mL
-------- =
AUC 281
g hr
mL
----------------- =
AUMC 2100
g hr
2
mL
------------------- =
V
d
11.4mL =
Cl 1.5
ml
hr
------ =
I.V. Bolus Dosing
9-(2-phophonylmethoxyethyl) adenine (Problem 4 - 18)
Naesens, Balzarini, and Clercq, "Pharmacokinetics in Mice of the Anti-Retrovirus Agent 9-(2-phophonylmethoxyethyl) adenine",
Drug Metabolism and Disposition (1992), p. 747- 752.
9-(2-phophonylmethoxyethyl) adenine (PEMA) is an anti-retrovirus (anti-HIV) agent. The pharmacokinetics of
PEMA in mice were established in a study by . In this study there were three different PEMA doses given: 25 mg/kg,
100 mg/kg, and 500 mg/kg. Each of these doses was injected intravenously into male mice. The data obtained from
study using the 25 mg/kg dose is summarized in the following table:
From the data presented in the preceding table, determine the following. (Assume that the mouse weighs 200g.)
3. Find .
4. Find .
PROBLEM TABLE 4 - 18. 9-(2-phophonylmethoxyethyl) adenine
Time (minutes)
Serum concentration
2.0 90.3
2.9 83.9
5.6 67.3
8.9 51.5
10.5 45.2
13.5 35.4
15.0 31.3
20.0 20.9
24.0 15.1
59.6 0.9
g
mL
--------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 18) Pema:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 10 20 30 40 50 60
Time (min)
10
-1
10
0
10
1
10
2
C
o
n

(
u
g
/
m
L
)

C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
I
C
/
M
L
)
k 0.08min
1
=
t
8.67min =
MRT 12.5min =
C
p
( )
0
105
g
mL
-------- =
AUC 1300
g hr
mL
----------------- =
AUMC 16250
g hr
2
mL
------------------- =
V
d
47.6ml =
Cl 3.8
mL
min
--------- =
I.V. Bolus Dosing
Thioperamide (Problem 4 - 19)
Sakurai, et. al., "The Disposition of Thioperamide, a Histamine H3-Antagonist, in Rats", J. Pharm. Pharmacol. (1994), p. 209 -
212.
Thioperamide is a histamine (H3) receptor-antagonist. In a study by Sakurai et al, rats were given 10 mg/kg intrave-
nous injections of Thioperamide. The following data was obtained from the study:
3. Find .
4. Find .
PROBLEM TABLE 4 - 19. Thioperamide
Time (minutes)
Serum concentration
3.7 3.1
7.5 2.8
13 2.4
45 1.1
60 0.74
120 0.16
g
mL
--------
k
t
MRT
C
p
( )
0
AUC
AUMC
V
d
Cl
I.V. Bolus Dosing
(Problem 4 - 19) thioperamide:
1.
2. .
3. .
4. .
5. .
6. .
7.
8. .
0 20 40 60 80 100 120
Time (min)
10
-1
10
0
10
1
C
o
n

(
u
g
/
m
L
)

C
O
N
C
E
N
T
R
A
T
I
O
N

(
M
I
C
/
M
L
)
k 0.0254min
1
=
t
27.3min =
MRT 39.4min =
C
p
( )
0
3.39
g
mL
-------- =
AUC 133.5
g min
mL
--------------------- =
AUMC 5256
g min
2
mL
----------------------- =
V
d
Dose
Cp
0
-------------
10
mg
kg
-------
3.39
g
mL
--------
mg
1000g
-------------------
1000mL
L
--------------------
-------------------------------------------------------------------- 2.95
L
kg
------ = = =
Cl 0.0254min
1
2.95
L
kg
------
1000ml
L
------------------ 75
mL
min kg
-------------------- = =
I.V. Bolus Dosing
Cocaine (Problem 4 - 20)
Khan,vM. et. al. Determination of pharmacokinetics of cocaine in sheep by liquid chromatography J. Pharm. Sci. 76:1 (39-43)
Jan 1987
I.V. Bolus Dosing
4.1.3 URINE
From the Laplace Transform of a drug given by IV bolus we find that :
(EQ 4-10)
where Xu is the cumulative amount of drug in the urine at time t. Rearranging, we
get:
(EQ 4-11)
where the amount of drug that shows up in the urine at infinite time, .
Thus a plot of vs. time on semi-log paper would result in a straight line
with a slope of -K1 and an intercept of .. and we can get k
u
from the intercept
and the slope. Rearranging the intercept equation, we get This
method of obtaining pharmacokinetic parameters is known as the Amount
Remaining to be Excreted (ARE) method.
TABLE 4-4 Enalapril urinary excretion data from 5 mg IV Bolus
Time (hr)
Cumulative
Enalapril in urine
(mg)
mg
1 0.41 0.59
2 0.65 0.35
3 0.80 0.20
4 0.88 0.12
6 0.96 0.04
1.0 ------
X
u
k
u
K1
------- X
0
1 e
K1 t ( )
( ) =
X
u
( )
X
u
k
u
K1
-------
,
_
X
0
e
K1t
=
X
u
( )
k
u
K1
------- X
0
=
X
u
( )
X
u
X
u
( )
k
u
K = 1
X
u
( )
X
0
--------------
X
u
X
u
I.V. Bolus Dosing

Utilizations: A.R.E.
Method
FIGURE 4-2. Cumulative Enalapril in urine
You should be able to transform a data set containing amount of drug in the urine vs. time into
cumulative amount of drug in the urine vs. time and plot the ARE. (Amount Remaining to be
Excreted -> vs. time on semi-log yielding a straight line with a slope of
and an intercept of
You should be able to determine the elimination rate constant, K1, from cumulative urinary
excretion data. (Calculate the slope of the graph on SL paper.)
You should be able to determine the excretion rate constant, ku, from cumulation urinary excre-
tion data. (Divide the intercept of the graph by X
0
and multiply by K1.
)
You should be able to determine .
You should be able to calculate percent metabolized or excreted from a data set. Thus,
Percent metabolized = and percent excreted unchanged = assuming
A second method is to plot the rate at which the drug shows up in the urine over
time. Again, using the LaPlace transforms, we find that:
(EQ 4-12)
Utilization: Rate of
excretion method
Thus, a plot of the rate of excretion vs. time results in a straight line on semi-log
paper with a slope of -K1 and an intercept, R
0
, of k
u
X
0
. Rearranging the intercept
0 1 2 3 4 5 6
10
10
10

X
u
(
i
n
f
)

-

X
u
0
-1
-2
Hours
1.3 hr
half life
0.2
0.1
X
u
( )
X
u cum ( )
{ }
K1 0.533 hr
1
= X
u
( )
k
u
X
0
K1
--------------- 1.0 mg = =
k
u
K = 1
X
u
( )
X
0
-------------- 0.53 hr
1 1.0 mg
5.0 mg
----------------- 0.106 hr
1
= =
k
m
K k
u
k
m
+ =
k
m
K1
------- 100
k
u
K1
------- 100
K k
u
k
m
+ =
dX
u
dt
--------- k
u
X
0
e
K1 t
R
0
e
K1 t
= =
I.V. Bolus Dosing
equation yields . In real data, we dont have the instantaneous excretion
rate , but the average excretion rate, , over a much larger interval. What
that means to our calculations is that over the interval of data collection, the total
amount of drug collected divided by the total time interval is the average rate. In
the beginning of the interval the rate was faster than at the end of the interval. So
the average rate must have occurred in the middle of the interval. Thus equation 4-
12 which is the instantaneous rate can be rewritten to
(EQ 4-13)
TABLE 4-5 Enalapril Urinary Rate Data
You should be able to transform a data set containing amount of drug in the urine vs. time inter-
val into Average Rate, , vs. ,(t mid the time of the midpoint of the interval), on semilog
yielding a straight line with a slope of and an intercept of . as shown below.
You should be able to determine extrapolate the line to . The value of Rate (at
), R
0
, = which when divided by .is k
r
.
Interval (hr) t(mid)
Enalapril in
urine ,(mg)
0-1 0.5 1 0.41 0.41
1-2 1.5 1 0.24 0.24
2-3 2.5 1 missed sample ?
3-4 3.5 1 0.08 0.08
4-6 5 2 0.08 0.04
k
u
R
0
X
0
------ =
t d
dX
u
X
u
t
----------
X
u
t
---------- k
u
X
0
e
K1 t
mid
R
0
e
K1 t
mid
= =
t
X
u
X
u
t
----------
X
u
t
---------- t
K1 k
u
X
0
0 1 2 3 4 5
10
-2
10
-1
10

T (Mid)
U
r
i
n
a
r
y

E
x
c
r
e
t
i
o
n

R
a
t
e

(
m
g
/
h
r
)
-1
-2
0
1.3 hr
half life
R0 = 0.53 mg/hr
k
u
t 0 =
t 0 = k
r
X
0
0.53 mg hr ( ) = X
0
I.V. Bolus Dosing
Thus,
You should be able to determine .
You should be able to calculate percent metabolized or excreted from a data set.
The rate equation is superior clinically because the ARE method requires collec-
tion of all of the urine which is usually only possible when you have a catheterized
patient while the Rate Method does not. (People dont urinate on command, and
your data could be in the toilet, literally.)
An additional advantage of the rate equations is that the has the units of
mass, which gives the total amount of drug excreted into the urine directly. Thus:
AN INTERESTING OBSERVATION: If you look at the LaPlace Transform of the
rate equation for any terminal compartment, you would see that the resulting equa-
tion is that of the previous compartment times the rate constant through which the
drug entered the terminal compartment. Thus, the rate of drug showing up in the
urine (terminal compartment) is:
where k
u
is the rate constant through which the drug entered the urine and
is the equation of the previous compartment.
R
0
X
0
------
0.53mg/hr
5mg
------------------------- 0.106hr
1
= =
k
m
K k
u
k
m
+ =
AUC
0
AUC
0
R
0
K1
-------
0.53 mg/hr
0.53 hr
1
-------------------------- 1 mg = = =
dX
u
dt
--------- k
u
X
0
e
K1 t
R
0
e
K1 t
= =
dX
dt
------- X
0
e
K1 t
=
I.V. Bolus Dosing
4.2 Metabolite
4.2.1 PLASMA
Remember, the LaPlace Transform of the metabolite data yielded
or depending
on which rate constant that we arbitrarily assigned to be K1, the summation of all
the ways that the drug is removed from the body and K2, the summation of all the
ways that the metabolite is removed from the body. When we begin to manipulate
the data, we know that we have a curve with two different exponents in it. (If they
were the same, the equation would be different.) We dont know which is bigger,
K1 or K2, but we can rewrite the equation to simply reflect K
large
and K
small
,
knowing that one is K1 and the other is K2 but not which is which. If we, then,
devided both sides of the equation by Vdm, the volume of distribution of the
metabolite, we would get :
(EQ 4-14)
Utilization:
Curve Stripping
You should be able to plot a data set of plasma concentration of metabolite vs. time on semi-log
paper yielding a bi-exponential curve.
as . And faster than . So, at some long
time, t, . In fact is small enough to be ignored. Thus at long
time, t, the equation becomes :
(EQ 4-15)
So that the plot of the terminal portion of the graph would yield a straight line with a slope of
-K
small
and an intercept of I =
You should be able to obtain the slope of the terminal portion of the curve, the negative of
which would be the smaller of the two rate constants, , (either the summation of all the
ways that the drug is eliminated, , or the summation of all the ways that the metabolite is
eliminated, ).
Subtracting the two previous equations yields
X
m
k
m
X
o
( )
K1 K2 ( )
------------------------- e
K 2t
e
K 1t
( ) = X
m
k
m
X
o
( )
K2 K1 ( )
------------------------- e
K 1t
e
K2t
( ) =
C
pm
k
m
K
l e arg
K
small
--------------------------------------
,

_ X
0
V
dm
----------
,

_
e
K
small
t ( )
e
K
l e arg
t ( )
,
_
=
e
Kt
0 t e
k
l e arg
t
0 e
k
small
t
0
e
K
l e arg
t
e
K
small
t
e
K
l e arg
t
C
pm
k
m
K
l e arg
K
small
-----------------------------------
,
_
X
0
V
dm
---------
,
_
e
K
small
t ( )
( ) =
k
m
K
l e arg
K
small
-----------------------------------
,
_
X
0
V
dm
---------
,
_
K
small
K1
K2
I.V. Bolus Dosing
(EQ 4-16)
which is a straight line on semi-log paper with a slope of -k
big
and an intercept of
. Note: we can get the larger of the two rate constants from this
method.
TABLE 4-6
In the above data Cp vs. Time is the plasma profile of the drug from Table 4-1 on page 2 and
Cpm1 vs. Time is the plasma profile of the metabolite. A plot of Cp vs. Time yielded a straight
line with a slope,(-K1) of -0.375 hr
-1
,

and

and intercept of 295
mic/L,
Drug Metabolite
(1) (2) (3) (4) (5)
Time (hr)
Cp
(mcg/L) Cpm1 (mcg/L)
0 0 181.2 181.2
0.5 24.7 175 150.3
1 44.4 168.9 124.5
2 139 71.8 157.5 85.7
4 65.6 96.5 136.9 40.4
6 31.1 100 119 19
8 14.6 94.7
12 76.5
24 34
C
pm
C
pm
k
m
K
l e arg
K
small
-----------------------------------
,
_
X
0
V
dm
---------
,
_
e
K
big
t ( )
( ) =
I
k
m
K
l e arg
K
small
------------------------------------
,
_
=
X
0
V
dm
---------
,
_
Cpm Cpm Cpm
K1
0.693
1.85 hr
1
---------------------- 0.375 hr
1
= =
I.V. Bolus Dosing
Figure 4-1 on page 3 (column 2 vs. 1 in Table 4-6 on page 52)
while a plot of Cpm1 vs. Time( Figure 4-3 on page 53) yields a biexponential plot with a termi-
nal slope of 0.07 hr
-1
, and extrapolating the terminal line back to time = 0
yields 181 mic/L.
FIGURE 4-3. Nifedipine Metabolite (column 3 vs. 1 in Table 4-6 on page 52)

0 2 4 6 8
Time (hours)
10
1
10
2
10
3
C
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
L
)

Cpo = 295 mic/L
C
o
n
c
e
n
t
r
a
t
i
o
n

(
m
i
c
/
L
)
Time (hr)
50
100
1.85 hr
k
small
0.693
10 hr
------------- =
Nifedipine IV bolus - Metabolite
Time (hours)
L
)

0 4 8 12 16 20 24
10
1
10
2
10
3
C
o
n
c
e
n
t
r
a
t
i
o
n

(
m
i
c
/
L
)
10 hr
80
40
Cpm0 181
mic
L
--------- =
I.V. Bolus Dosing
You should be able to feather (curve strip) the other rate constant out of the data by plotting the
difference between the extrapolated (to ) terminal line (column 4 vs. 1 in Table 4-6 on
page 52) and the observed data (at early times) (column 3 vs. 1 in Table 4-6 on page 52) yield-
ing a straight line with the slope of the line equal to the negative of the other (larger) rate con-
stant (column 5 vs. 1 in Table 4-6 on page 52).
First you would fill in the column (column 4 in Table 4-6 on page 52) by computing
for various values of time i.e where is the terminal slope of the
graph. Then (column 5 in Table 4-6 on page 52) would be column 4 - column 3.
Then a plot of vs. time (column 5 vs. 1 in Table 4-6 on page 52) is shown below.
FIGURE 4-4. Curve strip of Nifedipine Metabolite data
In this case, the slope of the stripped line line is -0.375 hr
-1
and the intercept is 0.181.2 mic/L.
The slope of -0.375 hr
-1
should not be surprising as the plot of the data in Figure 4-3 on page 53
resulted in a terminal slope of -.07 hr
-1
. Since the data set yielded a bi-exponential plot, sepa-
rating out the exponents could only yield K1 (0.375 hr
-1
) or K2 as determined by our Laplace
Transform information. Thus, the terminal slope could be either -K1 or -K2. Since it was obvi-
ously not -K1, it had to be -K2. Thus the other rate constant obtained by stripping has to be K1.
You can determine which slope is which rate constant if you have any data regarding intact drug
(i e. either plasma or urine time profiles of intact drug) as the slope of any of those profiles is
always .
You should be able to determine if you have any urine data regarding intact drug (i.e.
urine time profiles of intact drug) as the intercept of those profiles allow for the solution of .
Thus the intercept, I, of the extrapolated line of equation 4-14 could be rearranged to contain
only one unknown variable, .
t 0 =
Cpm Cpm
Cpm Cpm0 e
k
smal l
t
= k
small
Cpm Cpm
Cpm Cpm
0 1 2 3 4 5 6
10
1
10
2
10

Time (hr)
1
2
3
C
o
l
u
m
n

5
1.85 hr
Intercept
100
50
Half life
K1
V
dm
k
m
V
dm
k
m
X
0
K
l e arg
K
small
( ) I
-----------------------------------------------
0.375hr
1
25mg
1000 mic
mg
----------------------
0.375 0.07 ( ) hr
1
181.2
mic
L
---------
-------------------------------------------------------------------------- 170 L = = =
I.V. Bolus Dosing
Utilization:
MRT Calculations
You should be able to determine the rate constants using MRT calculations.
In a caternary chain, each compartment contributes its MRT to the overall MRT of the drug,
thus:
Flow Chart 2-4 IV Bolus
Suppose the drug were given by IV bolus. Then the drug would have to be metabolized and the
metabolite eliminated. Since the MRTs are additive, the overall MRT of the metabolite would
be made up of the MRTs of the two processes, thus:
Flow Chart 2-5 Metabolite
Thus, using the data from Table 4-3 on page 5 the MRT
(IV)Trap
is
hr or about hr using calculus.
And using the data from columns 1 and 3 from Table 4-6 on page 52 the MRT(met) using calcu-
lus is hr.
MRT
(elim)
= MRT
(met)
- MRT
(IV)
= 17 hr - 2.67 hr = 14.33 hr = 1/K2. Thus K2 = 0.07 hr
-1
.
X
K1
MRT(IV) = 1/K1
kmu km
Xm X
MRT(met) = MRT(elim)+MRT(IV)
MRT(met) = 1/K2 + 1/K1
MRT
AUMC
AUC
------------------ =
1986.1
819.9
---------------- 2.42 = = MRT
AUMC
AUC
------------------ =
2100
787
------------ 2.67 = =
MRT
AUMC
AUC
------------------ =
36000
2116
--------------- 17 = =
I.V. Bolus Dosing
4.2.2 URINE
Valid equations:
(EQ 4-17)
Utilization: as in the previous urinary rate equation, clinically we work with the average rate
over a definite interval which results in rewriting equation 4-17 as:
(EQ 4-18)
You should be able to plot a data set of rate of metabolite excreted vs. time (mid) on semi-log
paper yielding a bi-exponential curve.
You should be able to obtain the slope of the terminal portion of the curve, the negative of
which would be the smaller of the two rate constants (either or ).
You should be able to feather (curve strip) the other rate constant out of the data by plotting the
difference between the extrapolated (to ) terminal line and the observed data (at early
times) yielding a straight line with the slope of the line equal to the negative of the other (larger)
rate constant (either or ).
You should be able to utilize MRT calculations to obtain and .
You should be able to determine which slope is which rate constant if you have any data regard-
ing intact drug (i.e. either plasma or urine time profiles of intact drug) as the slope of any of
those profiles is always .
By this time, it should be apparent that data which fits the same shape curve
(mono-exponential, bi-exponential, etc.) are treated the same way. When the
curves are evaluated, the slopes and intercepts are obtained in the same manner.
The only difference is what those slopes and intercepts represent. These represen-
tations come from the equations which come from the LaPlace Transforms which
come from our picture of the pharmacokinetic description of the drug. Please
refer back to the section on graphical analysis in the Chapter 1, Math review for a
interpretation of slopes and intercepts of the various graphs.
Temporarily, please refer to exam section 1, chapter 14 for problems for this sec-
tion (until problems can be generated) as well as additional problems for the previ-
ous sections.
dX
mu
dt
-------------
k
mu
k
m
X
0
K
l e arg
K
small
( )
---------------------------------------- e
K
small
t
e
K
l e arg
t
{ } =
X
mu
t
-------------
k
mu
k
m
X
0
K
l e arg
K
small
( )
---------------------------------------- e
K
small
t
mid
e
K
l e arg
t
mid
{ } =
K1 K2
t 0 =
K1 K2
K1 K2
K1
CHAPTER 5 I.V. Infusion
OBJECTIVES
1. Given patient drug concentration and/or amount vs. time profiles, the student will
calculate (III) the relevant pharmacokinetic parameters available ( , K, , ,
, Clearance, MRT) from IV infusion data.
2. I.V. Infusion dosing for parent compounds
3. Plasma concentration vs. time profile analysis
4. Rate vs. time profile analysis
5. Professional communication of IV Infusion information
6. Computer aided instruction and simulation
7. Metabolite (active vs. inactive)
V
d
k
m
k
r
AUC
I.V. Infusion
5.1 Parent compound
5.1.1 PLASMA
Valid equations:
or (EQ 5-1)
(EQ 5-2)
at any time during the infusion
(EQ 5-3)
at steady state (t is long)
(EQ 5-4)
after termination of infusion
Where is the plasma concentration
is the infusion rate shown in equation 5-1 and equation 5-2.
is the plasma concentration when the
infusion is stopped.
Rewriting equation 5-4 to an equation which may be used by a computer results in:
(EQ 5-5)
where
and .
C
p
Q
K V
d
-------------- 1 e
Kt
( ) =
C
p
Dose
K V
d
T
infusion

--------------------------------------- 1 e
Kt
( ) =
C
p
( )
ss
Q
K V
d
-------------- =
C
p
C
p term ( )
e
Kt
=
C
p
Q
Dose
T
infusion
------------------- =
C
p term ( )
Q
K V
d
-------------- 1 e
Kt
infusion
( ) =
Cp
Q
K V
------------ e
K T
e
K T
( ) =
T
T T
i v
( ) = for T T
iv
> ( )
T
0 = for T T
iv
< ( )
I.V. Infusion
Using The Scientist
@
s Unit function makes the change in straight forward. In
The Scientist
@
, Unit(+) = 1 and Unit(-) = 0, so defining
meets these needs.
This equation is utilized in The Scientist
@
s companion product PKAnalyst
@
also
by MicroMath. Since the route of administration is an infusion and we would
know how much we gave (Dose), how fast we gave it (Q), and over how long the
infusion lasted (T
iv
), the only other variables in the equation are K and V
d
. PKAn-
alyst asks for T
iv
and yields DoverV ( ) and K as parameters resulting from
non-linear regression analysis. Dividing Dose by yields V
d
.
Utilization: You should be able to determine the infusion rate necessary to obtain a desired
plasma concentration. Rearranging equation 5-3 results in:
(EQ 5-6)
You should be able to determine how long it would take to get to a desired plasma
concentration. Using equation 5-1 and equation 5-3, it looks like it will take for-
ever to get exactly to steady state because in order for
, which occurs when . So,
how close is close enough? If , thats good enough in most
peoples estimation. So in order to find out how long it will take we use equation
5-1, setting and solve for time. Thus:
which results in

T
T T
iv
( ) UNIT T T
i v
( ) =
Dose
V
d
-------------
Dose
V
d
-------------
K V
d
C
p
( )
ss
Q =
C
p
( )
ss
Q
K V
d
--------------
Q
K V
d
-------------- 1 e
Kt
( ) = = e
Kt
0 t =
C
p
( ) 0.95 C
p
( )
ss
=
C
p
( ) 0.95 C
p
( )
ss
=
C
p
( ) 0.95 C
p
( )
ss
Q
K V
d
-------------- 1 e
Kt
( ) = =
0.95 1 e
Kt
( ) =
0.95 1 e
Kt
=
ln 0.05 ( ) Kt =
2.996 Kt =
I.V. Infusion
, (EQ 5-7)
or about 4.32 half lives to get to 95% of steady state. Generalizing, then, the num-
ber of half-lives it takes to get to steady-state is equal to the logarithm of the
inverse of how close is close (in this case, 5% or 0.05 = 20) devided by the loga-
rithm of two.
Changing infusion rates: Occasionally, it is necessary to change infusion rates to stabilize the patient. If a
patient were started on an infusion rate, Q1, and then at some subsequent time,
T>T*, the infusion rate was changed to Q2, the equation for the concentration after
the change would be:
(EQ 5-8)
Assuming equilibrium was reached at infusion rate Q1, we could simplify equation
5-8 by setting T = 0 at the time of the rate change (thus we would be interested in
the time after the change) resulting in:
(EQ 5-9)
Under these conditions, it would be useful to determine the time to reach the new
equilibrium. As before, within 5% is close enough. Thus if we are coming down
(lowering the Cp, i.e. Q2 < Q1), we would want and if we were
going up (raising the Cp, i.e. Q2 > Q1), we would want . Taking
the first condition we find:
(EQ 5-10)
Rearranging and solving for T results in:
(EQ 5-11)
Similarly, under the second condition, we would find:
2.996
K
---------------- t =
2.996
0.693
-------------t
1
2
-- -
4.32t
1
2
-- -
t = =
Cp
Q1
K V
------------ 1 e
K T
( )
( ) e
k T T
( ) ( )

Q2
K V
------------ 1 e
k T T
( ) ( )
( ) + =
Cp
Q1
K V
------------ e
k T
Q2
K V
------------ 1 e
k T
( ) + =
Cp 1.05
Q2
K V
------------ =
Cp 0.95
Q2
K V
------------ =
Cp 1.05
Q2
K V
------------
Q1
K V
------------ e
k T
Q2
K V
------------ 1 e
k T
( ) + = =
T
0.05 Q2
Q1 Q2
----------------------
,
_
ln
K
---------------------------------- =
I.V. Infusion
(EQ 5-12)
Combining equation 5-11 and equation 5-12 and rearranging results in:
(EQ 5-13)
Thus it is the absolute value of the difference of the two rates and the elimination
rate constant which determine the length of time needed to establish a new equilib-
rium. Under the conditions of , that is no previous infusion, and the dif-
ference is maximal equation 5-13 simplifies to equation 5-7. Under the conditions
of , the equation is undifined and has no utility (as well as makes no
sense, because the equation was designed to be used when there was a change in
rate.) However, , thus no change results in zero time to get to the new
equilibium. Similar to equation 5-7 as before, the generalization for the number of
half-lives it takes to obtain the new steady-state is the logarithm of (the fractional
difference of the rates (or the steady-state concentrations) times the inverse of how
close is close) devided by the logarithm of two.
As pharmacokinetic equations are additive, you should be able to determine a
loading dose (by I.V. bolus, for example) and a maintenance dose (infusion rate)
for a patient to extablish an equilibrium. If, for example, you want to give a load-
ing dose followed by an IV infusion, the generalization for the number of half-
lives it takes to obtain the new steady-state is the logarithm of (the fractional dif-
ference of the concentrations, Cp0 and Cpss, times the inverse of how close is
close) devided by the logarithm of two.
T
0.05 Q2
Q1 Q2
-------------------------
,
_
ln
K
------------------------------------- =
T
Q1 Q2
Q2
------------------------ 20
,
_
ln
K
----------------------------------------------
Q1 Q2
Q2
------------------------ 20
,
_
ln
0.693
---------------------------------------------- t
1 2
= =
Q1 0 =
Q1 Q2 =
T 0 =
Q2 Q1
lim
I.V. Infusion
Discussion: IV infusion is a controlled way to get drug into your patient. Using patient popula-
tion average pharmacokinetic parameters (K, V
d
) available in the drug mono-
graphs, you are able to make a professional judgement about:
1. the plasma concentration that you would like to achieve (from therapeutic range) and the time in
which you would like to get there.
2. the infusion rate necessary to get to the target concentration, and
3. the time necessary to to get there.
Example: Using
population average
pharmacokinetic
parameters to make
professional judgements.
As an example, theophylline is a bronchodilator used in asthma with a therapeutic
range of 10 to 20 mg/L, a volume of distribution of 0.45 (0.3 - 0.7) L/kg and a half
life of about 8 (6 - 13) hours for a non-smoking adult. Your patient weighs 200
pounds and meets these these criteria. The physician decides to maintain him at 15
mg/L. What do you do?
Using population average parameters for K and Vd, equation 5-6 results in:
.
For an eight hour IV infusion, you would need
of theophylline.
IV Theophylline comes as aminophylline which is theophylline compound con-
taining 85% theophylline and 15% ethylenediamine. So in order to get 425 mg of
theophylline we have to give
. So we
prepare our IV infusion using Aminophylline U.S.P. for injection (500 mg amino-
phylline in 20 mL) by placing the contents of the ampule in 1000 mL of D5W and
calculate the drip rate using an adult IV administration set which regulates the drip
to 10 gtts/mL. Thus the drip rate is:
0.693
8 hr
-------------
,
_
0.45
L
kg
------
kg
2.2 lb
-------------- 200 lb
,
_
15
mg
L
-------
,
_
53.2
mg
hr
------- =
53.2
mg
hr
------- 8 hr 425 mg =
425 mg theophylline
100 mg aminophylline
85 mg theophylline
------------------------------------------------------ 500 mg aminophylline =
1020 ml
8 hr
--------------------
hr
60 min
-----------------
10 gtts
ml
---------------- 21
gtts
min
---------
7 gtts
20 sec
---------------
I.V. Infusion
How long to get to steady
state?
After setting up the infusion, the doctor asks, How long to steady state?
Using equation 5-7, our patient who has an eight hour half life, will take about
to get to 95% of steady state. The patient doesnt want
relief in a day and a half. He needs to breathe NOW. What would you suggest?
Infusion takes too long.
How do we get relief
now? IV Bolus stat.
It might be possible to give him an IV Bolus dose stat which would get him to
right away. This is done by converting to
.

Converting to aminophylline yields:
. Thus,
if we gave a 725 mg IV bolus dose of aminophylline followed by a concomitant
IV infusion of 500 mg aminophylline over 8 hours, our patient should get to
steady state right away and stay there.
Some protocols require
starting with faster
infusion, then changing
to a slower one to get to
steady state faster.
Sometimes the physician might want to just increase the infusion rate (say double
it for a short time, 2Q) to get to the target concentration faster and then just back
the infusion down. If that is the protocol, the question becomes, How long do
you run the infusion in at the faster rate? Thus:
which yields and so
. Thus . Taking the ln of both sides
or that it will take one half-life to get to the target
plasma concentration (which is the Cp
ss
obtained by the infusion rate of 1Q) if you
run the infusion at a faster rate, 2Q. So for your patient, you might suggest an
infusion of 1000 mg over 8 hours (2Q for one half life) to get to steady state
quickly and then back off to 500 mg over 8 hours for the second 8 hours.
4.32 8 hr 34.6 hr =
C
p
( )
ss
C
p
( )
ss
Dose
V
d
------------- =
V
d
C
p
( )
ss
Dose =
0.45
L
kg
------
kg
2.2 lb
-------------- 200 lb
,
_
15
mg
L
-------
,
_
613.6 mg Theophylline =
613.6 mg Theophylline
100 mg aminophylline
85 mg theophylline
------------------------------------------------------ 725 mg aminophylline
C
p
( )
ss
Q
K V
d
--------------
2Q
K V
d
-------------- 1 e
Kt
( ) = = 1 2 1 e
Kt
( ) =
1
2
--- 1 e
Kt
=
1
2
--- 1 e
Kt
= ln 0.5 ( ) Kt =
ln 0.5 ( )
K
------------------
0.693
0.693
-------------t
1
2
-- -
t
1
2
-- -
t = = =
I.V. Infusion
Clearance: New
pharmacokinetic
parameter
Clearance is a pharmacokinetic parameter which relates the fraction
of the volume of distribution which is cleared of the drug per unit time. The vol-
ume of distribution is a mathematical construct which relates two knowns, the
Dose of the drug and the resultant Concentration. In linear kinetics, the Dose is
proportional to the Concentration. . The units of concentration are
while the units of dose are Mass. So the units of the proportionality con-
stant must be volume in order for the equation to balance. Thus, the volume of dis-
tribution is a hypothetical volume and not necessarily a real volume or
physiological space. Consequently, clearance is the hypothetical volume of fluid
from which the drug is irreversibly removed per unit time. So equation 5-3 can be
rewritten:
(EQ 5-14)
How do we calculate
Clearance from IV infu-
sion data?
and equation 5-14 can be rewritten to:
(EQ 5-15)
Thus, assuming steady state, the clearance can be calculated by dividing the infu-
sion rate by the resultant steady state plasma concentration.
How do we separate K
and V
d
out of Clear-
ance?
Graphing equation 5-4 which relates the decline in plasma concentration after ces-
sation of the infusion, the resultant slope of the line yields - K, the elimination rate
constant. Dividing the elimination rate constant, - K, obtained by equation 5-4 into
the clearance obtained by equation 5-15 results in the other necessary pharmacoki-
netic parameter, V
d
.
How can we utilize the
rate of change of
plasma concentration to
determine the pharma-
cokinetic parameters, K
and V
d
?
From our original model
(EQ 5-16)
and . Thus , . Rewriting equation 5-16 yields:
Cl K V
d
= ( )
C D
Mass
Volume
--------------------
C
p
( )
ss
Q
Cl
------ =
Cl
Q
C
p
( )
ss
--------------- =
t d
d
X Q K X ( ) =
Cp
X
V
d
------ = V
d
C p X =
I.V. Infusion
and rearranging and incorporating equation 5-1 yields
which can be simplified to
or
(EQ 5-17)
Thus a plot of vs. t ( actually, vs. exactly like we did in urinary
rate graphs) of the ascending portion of the plasma profile would result in a
straight line with a slope of -K and an intercept of .
t d
dC
p Q
V
d
------ K C
p
=
t d
dC
p Q
V
d
------ K
Q
K V
d
--------------
,
_
1 e
Kt
( ) =
t d
dC
p Q
V
d
------
Q
V
d
------
Q
V
d
------e
Kt
+ =
t d
dC
p Q
V
d
------e
Kt
=
t d
dC
p Cp
t
----------- t
mid
Q
V
d
------
I.V. Infusion
5.2 Problems
Equations needed for solving the problems:
1. k from the slope of the terminal portion of the graph of Cp vs. T
2.
3. Volume of distribution from
4. Clearance
5. You wish to maintain a plasma concentration of Cp
ss
.
a. Calculate the infusion rate necessary to maintain
Cp
ss
.
b. Suggest a loading dose which would give you Cp
ss
immediately.

c. How long will it take to reach steady state?

d. Find the plasma concentration if the infusion is discontinued at time = T
dc
hours.
.
e. Find the plasma concentration T
post
hours after infusion is discontinued at time = T
dc
hours.

t
1 2
0.693
k
------------- =
Cp
Q
K V
d
-------------- 1 e
Kt
( ) =
Cl K V
d
=
Q Cp
ss
K V
d
=
Dose
loading
Cp
ss
V
d
=
T
95
4.32 T
1 2
=
Cp
dc
Q
K V
d
-------------- 1 e
K T
dc
( )
( ) =
Cp
post
Cp
dc
e
K T
post
( )
=
I.V. Infusion
Acyclovir (Problem 5 - 1)
Laskin, O., "Clinical pharmacokinetics of acyclovir", Clinical Pharmacokinetics (1983), p. 187 - 201.
Acyclovir (225.21 g/Mole) is an antiviral drug used in the treatment of herpes simplex, varicella zoster, and in suppres-
sive therapy. In this study, patients were given varying doses of acyclovir over one hour by infusion. Acyclovir distrib-
utes uniformly into the plasma and tissues such that the plasma concentration is representative of tissue concentration.
Acyclovir is 30% metabolized and 70% renally excreted. The following data was obtained from an intravenous infu-
sion dose of 2.5 mg/kg over one hour where the patient weighed 70 kg.
From this data determine the following:
1. k
2.
3. Volume of distribution
4. Clearance
5. You wish to maintain a plasma concentration of 25 .
a. Calculate the infusion rate necessary to maintain a plasma concentration of 25
b. Suggest a loading dose for the patient which would give you Cpss immediately.
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours.
PROBLEM TABLE 5 - 1. Acyclovir
Time (hours)
Plasma concentration
0 0
0.25 7
0.5 12
0.75 17
1 20
2 10
3 5
5 1
umol
L
-------------
,
_
t
1 2
umol L
umol L
I.V. Infusion
Acyclovir on page 11
1. k = 0.751 hr
-1
(from slope of graph).
2. = 0.923 hr (from slope of graph).
3. Volume of distribution = 26.2 L
4. Clearance = 19.67 l/hr
5. You wish to maintain a plasma concentration of 25 .
a. Calculate the infusion rate necessary to maintain a plasma concentration of 25 = 111 mg/hr
b. Suggest a loading dose for the patient which would give you Cpss immediately. 148 mg
c. How long will it take to reach steady state? 4 hr
d. Find the plasma concentration if the infusion is discontinued at time = 5 hours. = 25
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 5 hours. = 5.6

0 1 2 3 4 5
10
0
10
1
10
2
C
o
n
c
e
n
t
r
a
t
i
o
n
Time
t
1 2
umol L
umol L
umol L
umol L
I.V. Infusion
Aminophylline (Problem 5 - 2)
Gilman, T., et al., "Estimation of theophylline clearance during intravenous aminophylline infusions", Journal of Pharmaceutical
Sciences (May 1985), p. 508 - 514.
Aminophylline is used in the treatment of bronchospasm. In this study, aminophylline was given by intravenous infu-
sion to patients with a mean weight of 75.7 kg. The doses given were chosen to maintain a between 10 -20 mg/L based
on desirable body weight. The doses were given at a rate of 0.5 mg/kg/hour (Theophylline) for 84 hr. The following
set of data was collected.
1. k 2.
3. Volume of distribution 4. Clearance
5. 6. You wish to maintain a plasma concentration of 15 mg/L in your patient.
a. Calculate the infusion rate necessary to maintain a plasma concentration of 15 mg/L.
Problem Submitted By: Maya Leicht AHFS 12:12.00 Sympathomimetics
Problem Reviewed By: Vicki Long GPI: 4430001000 Xanthine Sympathomimetic
PROBLEM TABLE 5 - 2. Aminophylline
Time (hours)
0 0.
6 5
12 8
24 11
30 11.6
36 12.0
48 12.4
54 12.5
66 12.6
72 12.8
84 12.8
88 9
92 6.4
96 4.6
100 3.2
mg
L
-------
,
_
t
1 2
I.V. Infusion
Aminophylline on page 13
1. = 0.085 hr
-1
2. = 8.15 hr
3. V
d
= 35.3 L
4. Cl = 3 L/hr
5a. = 45 mg/hr
5b. = 530 mg
5c. = 35 hr
5d. = 5.2 mg/L
5e. = 4.4 mg/L

0 20 40 60 80 100
10
10
10
C
O
N
C
E
N
T
R
A
T
I
O
N
0
1
2
Time
k
t
1 2
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Carmustine (Problem 5 - 3)
Henner, W., et al., "Pharmacokinetics and immediate effects of high-dose carmustine in man", Cancer Treatment Reports vol.70
(1986), p. 877 - 880.
Carmustine (BCNU) is an antineoplastic agent with a molecular weight of 214.04 g.
In this study a 70 kg, 1.8 M
2
patient was given 600 by intravenous infusion over 2 hours. The following data
was obtained.
1. k
2.
3. V
d
4 Cl
5. A patient with a BSA of1.8 is to be given BCNU by IV infusion. You wish to maintain a plasma
concentration of 2 . Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 2 .
d. Find the plasma concentration if the infusion is discontinued at time = 10 minutes.
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 10 minutes.
Problem Submitted By: Maya Leicht AHFS 10:00.00 Antineoplastics
Problem Reviewed By: Vicki Long GPI: 2110201000 Antineoplastics, Nitrosoureas
PROBLEM TABLE 5 - 3. Carmustine
Time (minutes)
15 .3
30 .5
60 .7
90 .75
120 .8
135 .5
142.5 .4
150 .3
mg m
2
mg
L
-------
t
1 2
M
2
uM
uM
I.V. Infusion
Carmustine on page 15
1. k = 0.031 min
-1
2. = 22 min
3. V
d
= 198 L/M
2
4 Cl = 6.15 L/M
2
/hr
5. A patient with a BSA of1.8 is to be given BCNU by IV infusion. You wish to maintain a plasma
concentration of 2 . Determine the following:
c. How long will it take to reach steady state? 4.32 * T 1/2 = 97 min.
d. Find the plasma concentration if the infusion is discontinued at time = 10 min. = 0.1197 mg/L
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 10 min. = 0.017 mg/L
C
O
N
C
E
N
T
R
A
T
I
O
N
TIME

0 50 100 150
10
10
-1
0
t
1 2
M
2
uM
uM
Q Cp
ss
V
d
K
2mole
L
-------------------
214g
mole
----------------
mg
1000g
-------------------
198L
M
2
------------ 1.8M
2
0.031min
1 4.73mg
min
------------------
285mg
hr
----------------- = = =
Dose Cp
ss
V
d
2mole
L
-------------------
214g
mole
----------------
mg
1000g
-------------------
198L
M
2
------------ 1.8M
2
150mg = = =
I.V. Infusion
Cefotaxime (Problem 5 - 4)
Kearns, G., Young, R., and Jacobs, R., "Cefotaxime dosage in infants and children--pharmacokinetic and clinical rationale for an
extended dosage interval", Clinical Pharmacokinetics (1992), p. 284 - 297.
Cefotaxime is a third generation cephalosporin which is widely used as an antimicrobial in neonates, infants, and chil-
dren. In this study, infants and children were given a 50 mg/kg dose of cefotaxime intravenously over 0.25 hour. The
following data was collected:
From this data, assuming that the patient weighs 30 kg, determine the following:
1. k
2.
3. V
d
4. Cl
5. You wish to maintain a plasma concentration of 80 mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 80mg/L
d. Find the plasma concentration if the infusion is discontinued at time = 0.25 hours.
Problem Submitted By: Maya Leicht AHFS 08:12.06 Cephalosporins
Problem Reviewed By: Vicki Long GPI: 0230007510 Cephalosporins - 3rd Generation
PROBLEM TABLE 5 - 4. Cefotaxime
Time (hours)
0.00 0
0.05 35
0.10 70
0.20 140
0.35 155
0.60 130
0.85 110
1.20 80
1.30 75
2.00 45
2.40 35
3.40 15
4.50 8
6.50 1.7
mg
L
-------
,
_
t
1 2
I.V. Infusion
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 0.25 hours.
Cefotaxime on page 17
1. = 0.733 hr
-1
2. = 0.945 hr
3. V
d
= 0.276 L/kg
4. Cl = 0.202 L/kg/hr
4a. = 16.2 mg/kg/hr
4b. = 22.1 mg/kg
4c. = 4.1 hr
4d. = 13.35 mg/L
4e. = 3.09 mg/L

0 1 2 3 4 5 6 7
10
0
10
1
10
2
10
3
C
O
N
C
E
N
T
R
A
T
I
O
N
TIME
k
t
1 2
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Ganciclovir (Problem 5 - 5)
Trang, J., et al., "Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections",
Clinical Pharmacology and Therapeutics (1993), p. 15 - 21.
Ganciclovir is used against the human herpes viruses, cytomegalovirus retinitis, and cytomegalovirus infections of the
gastrointestinal tract. In this study, twenty-seven newborns with cytomegalovirus disease were given 4 mg/kg of ganci-
clovir intravenously over one hour. Blood samples were taken and the data obtained is summarized in the following
table:
1. k
2.
3. V
d
4. Cl
4. A patient is to be given ganciclovir by IV infusion to an infant weighing 6.1 kg. You wish
to maintain a plasma concentration of 5.5 mcg/mL. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 5.5mcg/mL.
d. Find the plasma concentration if the infusion is discontinued at time = 1 hour.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 1 hour.
PROBLEM TABLE 5 - 5. Ganciclovir
Time (hours)
0.5 3.10
1.5 4.50
2.0 3.80
3.0 2.90
4.0 2.30
6.0 1.50
8.0 0.88
ug
mL
--------
,
_
t
1 2
I.V. Infusion
Ganciclovir on page 19
1. = 0.255 hr
-1
2. = 2.72 hr
3. V
d
= 0.687 L/kg
4. Cl = 0.175 L/kg/hr
5a.
5b.
5c.
5d.
5e.

0 2 4 6 8
10
-1
10
0
10
1
Time
C
O
N
C
E
N
T
R
A
T
I
O
N
k
t
1 2
Q Cp
ss
V
d
K
5.5g
ml
--------------
mg
1000g
-------------------
1000ml
L
------------------
0.687L
kg
----------------- 6.1kg
,
_
0.255
hr
-------------
5.9mg
hr
--------------- = = =
D
L
Cp
ss
V
d
5.5g
ml
--------------
mg
1000g
-------------------
1000ml
L
------------------
0.687L
kg
----------------- 6.1kg
,
_
23mg = = =
T
ss
95%
4.32 t
1 2
11.75hr = =
C
p
term
Q
K V
d
-------------- 1 e
Kt
( ) =
5.9mg
hr
---------------
0.255
hr
-------------
0.687L
kg
----------------- 6.1kg
------------------------------------------------------ 1 e
K 1hr
( )
1.24mg
L
------------------ = =
C
p
C
p
term
e
K 2hr 1.24mg
L
------------------ 0.6
0.74mg
L
------------------ = = =
I.V. Infusion
Gentamicin (Problem 5 - 6)
Kaojarern, S., et al., "Dosing regimen of gentamicin during intermittent peritoneal dialysis", Journal of Clinical Pharmacology
(1989), p. 140 - 143.
Gentamicin is an aminoglycoside antibiotic which is frequently used in the treatment of gram-negative bacilli infec-
tions. Since it has a low therapeutic index, it is important to determine proper dosage regimens. In this study, patients
on peritoneal dialysis received a 30 minute intravenous infusion of 80 mg gentamicin in 100 mL of 5% dextrose in
water. The following data was collected:
1. k
2.
3. Vd
4. Cl
5. A patient is to be given gentamicin by IV infusion. You wish to maintain a plasma concentration
of 5.2 . Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 5.2
d. Find the plasma concentration if the infusion is discontinued at time = 0.5 hours.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 0.5 hours.
Problem Reviewed By: Vicki Long GPI: 0700002010 Aminoglycosodes
PROBLEM TABLE 5 - 6. Gentamicin
Time (hours)
0.50 5.68
1.50 5.15
3.70 4.80
7.35 3.99
11.30 3.35
24.00 2.02
ug
mL
--------
,
_
t
1 2
ug mL
ug mL
I.V. Infusion
Gentamicin on page 21
1. = 0.0431 hr
-1
2. = 16.1 hr
3. = 14.5 L
4. Cl =0.625 L/hr
5a. = 3.25 mg/hr
5b. = 75 mg
5c. = 69.6 hr
5d. = 0.11 mg/L
5e. = 0.10 mg/L

0 5 10 15 20 25
10
0
10
1
C
O
N
C
E
N
T
R
A
T
I
O
N
Time
k
t
1 2
V
d
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Human Monoclonal Anti-lipid A antibody (HA-1A) (Problem 5 - 7)
Fisher, C., et al., "Initial evaluation of human monoclonal anti-lipid A antibody (HA-1A) in patients with sepsis syndrome", Criti-
cal Care Medicine (1990), Vol.18, No. 12, p. 1311 - 1315.
HA-1A is an immunoglobulin antibody. In this study, patients received a 250 mg intravenous infusion of HA-1A over
15 minutes. Serum levels were measured before and after infusion and the following data was collected:
1. k
2.
3. Vd
4. Cl
5. A patient is to be given HA-1A by IV infusion. You wish to maintain a plasma concentration of 100 g/mL.
Determine the following:
Problem Submitted By: Maya Leicht AHFS 24:06.00 Antilepemics
Problem Reviewed By: Vicki Long GPI: 3900000000 Antihyperlipidemic
PROBLEM TABLE 5 - 7. Human Monoclonal Anti-lipid A antibody (HA-1A)
Time (hours)
0.00 0
0.75 80
1.00 75
2.00 74
5.00 65
15.00 50
25.00 40
48.00 21
72.00 10
ug
mL
--------
,
_
t
1 2
ug mL
I.V. Infusion
Human Monoclonal Anti-lipid A antibody (HA-1A) on page 23
1. = 0.0282 hr
-1
2. = 24.4 hr
3. = 3.2 L
4. = 0.09 L/hr
5a. = 9 mg/hr
5b. = 320 mg
5c. = 105 hr
5d. = 2.78 mg/L
5e. = 2.56 mg/L

0 20 40 60 80
10
1
10
2
C
O
N
C
E
N
T
R
A
T
I
O
N
Time
k
t
1 2
V
d
Cl
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Ifosfamide (Problem 5 - 8)
Lewis, L., "The pharmacokinetics of ifosfamide given as short and long intravenous infusions in cancer patients", British Journal
of Clinical Pharmacology Vol. 31 (1991), p. 77 - 82.
Ifosfamide is an agent which has shown some pharmacological response in the treatment of cancer. In this study, a 5
dose of ifosfamide was infused over 30 minutes. The median BSA for the subjects was 1.8 . The
following data was obtained:
1. k
2.
3. Vd
4. Cl
5. A patient is to be given ifosfamide by IV infusion. The patient has a BSA 1.8 M
2
. You wish to maintain a
plasma concentration of 336 g/mL. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 336
d. Find the plasma concentration if the infusion is discontinued at time = 20 min.
e. Find the plasma concentration 2 hours after infusion is discontinued at time = 20min.
PROBLEM TABLE 5 - 8. Ifosfamide
Time (hours)
0 0.0
0.5 285.0
1 260.0
2 220.0
4 160.0
6 112.0
8 80.0
10 60.0
24 5
g m
2
m
2
ug
mL
--------
,
_
t
1 2
ug mL
I.V. Infusion
Ifosfamide on page 25
1. = 0.1716 hr
-1
2. = 4.04 hr
3. = 16.6 L/M
2
4. = 2.85 L/hr/M
2
5a. = 1.725 g/hr
5b. = 10 g
5c. = 17.5
5d. = 18.7 mg/L
5e. = 13.25 mg/L
0 5 10 15 20 25
10
0
10
1
10
2
10
3
C
O
N
C
E
N
T
R
A
T
I
O
N
Time
k
t
1 2
V
d
Cl
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Isosorbide 5-mononitrate (Problem 5 - 9)
Major, R., et al., "Isosorbide 5-mononitrate kinetics" (1983), p. 653- 660.
Isosorbide 5-mononitrate (5-ISMN) is a metabolite of isosorbide dinitrate. In this study, the kinetics of isosorbide 5-
mononitrate were looked at in 12 healthy patients after an intravenous infusion of 20 mg at 8 mg/hour for 2.5 hours.
This drug follows one-compartment, open model kinetics. The following data was collected:
1. k 2.
3. Vd 4. Cl
5. A patient is to be given 5-ISMN by IV infusion. You wish to maintain a plasma concentration
of 300 ng/mL. If the volume of distribution of 5-ISMN is 44.5, determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 300 ng/mL.
PROBLEM TABLE 5 - 9. Isosorbide 5-mononitrate
Time (hours) Plasma concentration (ng/mL)
0.25 40
0.50 91
0.75 141
1.00 181
1.50 239
2.00 305
2.50 351
3.00 335
3.50 303
4.50 257
5.50 216
7.50 162
9.50 117
11.50 77
14.50 47
18.50 24
26.50 7
t
1 2
I.V. Infusion
Isosorbide 5-mononitrate on page 27
1. = 0.168 hr
-1
2. = 4.125 hr
3. = 44.6 L
4. = 7.5 L/hr
5a. = 2.25 mg/hr
5b. = 13.4 mg
5c. = 17.8 hr
5d. = 46.4 ng/mL
5e. = 33.2 ng/mL
0 5 10 15 20 25 30
10
0
10
1
10
2
10
3
C
O
N
C
E
N
T
R
A
T
I
O
N
Time
k
t
1 2
V
d
Cl
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Moclobemide (Problem 5 - 10)
Schoerlin, M., et al., "Disposition kinetics of moclobemide a new MAO-A inhibitor, in subjects with impaired renal function", Jour-
nal of Clinical Pharmacology Vol 30 (1990), p. 272 - 284.
Moclobemide is reversibly inhibits the A-isozyme of the monoamine oxidase enzyme system. In this study, twelve
patients received a 96.7 mg dose as an intravenous infusion over 20 minutes. Blood samples were obtained during the
infusion and after the infusion was ended and the following data was obtained:
1. k
2.
3. Vd
4. Cl
5. A patient is to be given moclobemide by IV infusion. You wish to maintain a plasma concentration
of 1mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 1mg/L.
d. Find the plasma concentration if the infusion is discontinued at time = 15 min.
PROBLEM TABLE 5 - 10. Moclobemide
Time (hours) Plasma concentration (mg/L)
0.0 0.000
0.2 0.6
0.4 1
0.7 0.85
0.9 0.750
1.2 0.70
1.6 0.60
1.9 0.50
2.4 0.40
3.4 0.25
4.5 0.15
5.5 0.10
6.4 0.070
t
1 2
I.V. Infusion
e. Find the plasma concentration 3 hours after infusion is discontinued at time = 15 mins.
Moclobemide on page 29
1. = 0.44 hr-1
2. = 1.6 hr.
3. = 90.4 L
4. = 39.8 L/hr
5a. = 40 mg/hr
5b. = 90 mg
5c. = 6.8 hr
5d. = 0.1 mg/L
5e. = 0.028 mg/L

0 1 2 3 4 5 6 7
10
-2
10
-1
10
0
C
O
N
C
E
N
T
R
A
T
I
O
N
Time
k
t
1 2
V
d
Cl
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Obidoxime (Problem 5 - 11)
Bentur, Y., et al., "Pharmacokinetics of obidoxime in organophosphate poisoning associated with renal failure", Clinical Toxicol-
ogy (1993), Vol. 31, p. 315 - 322.
Obidoxime is an agent which is used as an antidote in organophosphate poisoning. In this study, the pharmacokinetics
of obidoxime were studied in a 20 year old patient who attempted to commit suicide by ingesting Tamaron (60% meth-
amidophos, an organophosphate, in ethylene glycol monethyl ether). She was given 4 mg/kg Obidoxime by intrave-
nous infusion over 10 minutes and the following data was collected:
1. k
2.
3. Vd
4. Cl
5. A patient is to be given obidoxime by IV infusion. The patient has a body weight of 60 kg.
You wish to maintain a plasma concentration of 10 g/mL. Determine the following:
PROBLEM TABLE 5 - 11. Obidoxime
Time (minutes)
5 9
10 18
15 17
30 16
45 15
60 14
90 12
120 11
150 9.3
180 8
240 6.1
300 4.6
g mL
t
1 2
ug mL
I.V. Infusion
e. Find the plasma concentration 1 hour after infusion is discontinued at time = 30 minutes.
Obidoxime on page 31
1. = 0.00463 min-1
2. = 150 min
3. = 0.22L/kg
4. = 1 mL/min
5a. = 0.61 mg/min
5b. = 132 mg
5c. = 10.8 hr
5d. = 1.3 mg/L
5e. = 0.98 mg/L

0 50 100 150 200 250 300
10
0
10
1
10
2
C
O
N
C
E
N
T
R
A
T
I
O
N
Time
k
t
1 2
V
d
Cl
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Perindoprilat (Problem 5 - 12)
Macfadyen, R., Lees, K., and Reid, J., "Studies with low dose intravenous diacid ACE inhibitor (perindoprilat) infusions in normo-
tensive male volunteers", Journal of Pharmaceutical Sciences (1991), p. 115 - 121.
Perindoprilat and other ACE inhibitors are used in the management of hypertension and chronic congestive heart fail-
ure. In this study, a 1 mg dose was infused over a one hour period. The following data was collected:
1. k
2.
3. Vd
4. Cl
5. A patient is to be given perindoprilat by IV infusion. You wish to maintain a plasma concentration
of 30 ng/ml. Determine the following:
a. Calculate the infusion rate necessary to maintain a plasma concentration of 30 ng/mL.
PROBLEM TABLE 5 - 12. Perindoprilat
Time (minutes)
5 4.0
10 9.0
20 16.0
30 24.0
40 30.0
50 36.0
60 42.0
65 40.0
70 38.0
80 35.0
90 32.0
100 29.0
110 27.0
120 24.0
ng mL
t
1 2
I.V. Infusion
Perindoprilat on page 33
1. = 0.0087 min
-1
2. = 79.6 min
3. = 18.9 L
4. =164 mL/min
5a. = 5 g/min
5b. = 0.57 mg
5c. = 5.73 hr
5d. = 27.8 ng/mL
5e. = 9.8 ng/mL

0 20 40 60 80 100 120
10
0
10
1
10
2
C
O
N
C
E
N
T
R
A
T
I
O
N
Time
k
t
1 2
V
d
Cl
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Sulfonamides (Problem 5 - 13)
Boddy, A., Edwards, P., and Rowland, M., "Binding of sulfonamides to carbonic anhydrase: influence on distribution within blood
and on pharmacokinetics", Pharmaceutical Research (1989), p. 203- 209
This study looks at the affinity of sulfonamides for carbonic anhydrase. Doses of 8 micromoles/kg were administered
via the jugular vein cannula in approximately 0.5 mL of PEG 400 over 5 minutes at a constant rate. Samples were col-
lected during the infusion period and for 30 minutes afterward. The following set of data was collected:
1. k
2.
3. Vd
4. Cl
5. A 70-kg patient is to be given a sulfonamide by IV infusion. You wish to maintain a plasma
concentration of 30 M. Determine the following:
a. Calculate the infusion rate which would be necessary to maintain the plasma concentra-
tion of 30 M.
PROBLEM TABLE 5 - 13. Sulfonamides
Time (minutes)
2.0 17.0
4.0 31.0
5.0 37.0
7.5 32.0
9.0 28.0
12.0 22.5
15.0 18.0
18.0 14.0
23.0 11.0
30.0 6.5
35.0 4.5
M ( )
t
1 2
I.V. Infusion
e. Find the plasma concentration 30 minutes after stopping infusion at time = 4 hours.
Sulfonamides on page 35
1. = 0.0705 min
-1
2. = 9.8 min
3. = 0.18 L/kg
4. = 12.7 mL/min/kg
5a. = 26.9 mole/min
5b. = 380 mole
5c. = 42 min
5d. = 30 mole/L
5e. = 3.6 mole/L

0 5 10 15 20 25 30 35
10
0
10
1
10
2
C
O
N
C
E
N
T
R
A
T
I
O
N
Time
k
t
1 2
V
d
Cl
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Terodiline (Problem 5 - 14)
Hallen, B. ,et al., "Bioavailability and disposition of terodiline in man", Journal of Pharmaceutical Sciences (1994), p. 1241 -
1246.
Terodiline is an agent which works as an anticholinergic and a calcium antagonist. It is used to treat incontinence. It
is metabolized into p-Hydroxyterodiline, which is further metabolized to 3,4-dihydroxyterodiline. The parent drug and
all of its metabolites are excreted into the urine as well as the feces. A patient is given 12.5 mg of Terodiline by IV
infusion at a rate of 1 mL/ minute for 5 minutes. The following data is collected:
1. k
2.
3. Vd
4. Cl
5. A patient is to be given terodiline by IV infusion. You wish to maintain a plasma concentration
of 40 mcg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of40 mcg/L.
e. Find the plasma concentration 2 hours after stopping infusion if the infusion ended at
time = 5 hours.
PROBLEM TABLE 5 - 14. Terodiline
Time (hours)
25.000 31
50.000 23
75.000 15
100.000 12
125.000 8
150.000 6
175.000 4
200.000 3
225.000 2
g L
t
1 2
I.V. Infusion
Terodiline on page 37
1. = 0.0136 hr
-1
2. = 50.9 hr
3. = 283 L
4. =3.85 L/hr
5a. = 0.154 mg / hr
5b. = 11.32 mg
5c. = 220 hr
5d. = 2.63 g/L
5e. = 2.56 g/L

0 50 100 150 200 250
10
0
10
1
10
2
C
O
N
C
E
N
T
R
A
T
I
O
N
Time
k
t
1 2
V
d
Cl
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Tinidazole (Problem 5 - 15)
Robson, R., Bailey, R., and Sharman, J., "Tinidazole pharmacokinetics in severe renal failure", Clinical Pharmacokinetics (1984),
p. 88 - 94.
Tinidazole is an antimicrobial similar to metronidazole which is used in the treatment of trichomoniasis, giardiasis,
amoebiasis, and anaerobic infections. This study focuses on the pharmacokinetics of tinidazole in patients suffering
from severe renal failure. Twelve patients received 800 mg of tinidazole dissolved in 400 mL of dextrose monohydrate
solution as an intravenous infusion at a rate of 60 mg/min. Blood samples were taken and the following data was
obtained:
1. k
2.
3. Vd
4. Cl
5. A patient is to be given tinidazole by IV infusion. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of 25 mg/L.
e. Find the plasma concentration 2 hours after stopping infusion if the infusion was stopped
at time = 1 hour.
PROBLEM TABLE 5 - 15. Tinidazole
Time (hours) Plasma concentration (mg/L)
1 14.9
3 13.1
6 11.2
12 8.9
24 5.1
48 2.1
t
1 2
I.V. Infusion
Tinidazole on page 39
1. = 0.04136 hr-1
2. = 16.75 hr
3. = 54.7 L
4. = 2.26 L/hr
5a. = 56.6 mg/hr
5b. = 1.37 g
5c. = 72.4 hr
5d. = 1 mg/L
5e. = 0.93 mg/L

0 10 20 30 40 50
10
0
10
1
10
2
C
O
N
C
E
N
T
R
A
T
I
O
N
Time
k
t
1 2
V
d
Cl
Q
D
L
t
ss
95%
C
p
C
p
I.V. Infusion
Tobramycin (Problem 5 - 16)
Cooney, G., et al., "Absolute bioavailability and absorption characteristics of aerosolized tobramycin in adults with cystic fibro-
sis", Journal of Clinical Pharmacology Vol. 34, (1994), p. 255- 259.
Most persons with cystic fibrosis (CF) become colonized with Pseudomonas aeruginosa in their bronchial secretions
within their second decade of life. These patients require frequent treatment with potent anti-pseudomonal antibiotics
such as Tobramycin. In this study, an intravenous infusion of 2.5 mg/kg tobramycin was given over 35 minutes. The
following data was collected:
1. k
2.
3. Vd
4. Cl
5. A patient is to be given tobramycin by IV infusion. The patient has a body weight of 70 kg. You wish
to maintain a plasma concentration of 10 mg/L. Determine the following:
a. Calculate the infusion rate necessary to maintain the plasma concentration of 10 mg/mL.
e. Find the plasma concentration 1 hour after stopping infusion if the infusion wasstopped at
time = 30 minutes.
PROBLEM TABLE 5 - 16. Tobramycin
Time (minutes)
35 8.00
60 6.00
90 4.50
150 2.50
270 0.75
mg
L
-------
,
_
t
1 2
I.V. Infusion
Tobramycin on page 41
1. = 0.01 min-1
2. = 69.3 min
3. = 0.269 L/kg
4. = 2.7 mL/min
5a. = 0.027mg/kg/min = 1.62 mg/kg/hr
5b. = 2.7 mg/kg
5c. = 300 min = 5 hr
5d. = 2.6 mg/L
5e. = 1.43 mg/L
0 50 100 150 200 250 300
10
-1
10
0
10
1
C
O
N
C
E
N
T
R
A
T
I
O
N
Time
k
t
1 2
V
d
Cl
Q
D
L
t
ss
95%
C
p
C
p
CHAPTER 6 Biopharmaceutical Factors
Author: Michael Makoid
OBJECTIVES
After successfully completing this chapter, the student shall understand:
1. Physiology and machanisms of absorbtion
2. Effects of diffusion, cardiac output / blood perfusion, physical properties of the
drug and body on distribution
3. Biotransformation, first pass effect, and clearance
4. Renal, biliary, mammary, salivary, other forms of excretion.
5. identify the effects of physiological changes with age, sex, and disease on the
absorption, distribution, metabolism, and excretion of a drug.
CHAPTER 7 Oral Dosing
OBJECTIVES
After successfully completing this chapter, the student shall be able to
1. Given patient drug concentration and/or amount vs. Time profiles, the student will
calculate (III) the relevant pharmacokinetic parameters ( , K, , , , ,
Clearance, MRT, MAT) available from oral data.
calculate (III) the K from the terminal portion of the curve.
calculate (III) the from either the curve stripping Moment techniques.
calculate (III) the Absolute Bioavailability from comparing IV and oral (or
some other process which involves absorption) data.
calculate (III) the Comparative Bioavailability from comparing the generic to the
inovator product.
qualitatively evaluate (IV) bioequivalence as determined by rate of absorption
(peak time) and extent of absorption (Area Under the Curve - AUC, and ).
evaluate (IV) bioequivalence data.
lucidly discuss (IV) bioequivalence and recommend (V) to another competant
professional if s/he believes products to be equivalent.
V
d
k
m
k
r
k
a
AUC
k
a
C
p
( )
max
Oral Dosing
9. The student shall be able to properly use vocabulary relative to bioequivalence.
Oral Dosing
7.1 Oral dosing
7.1.1 VALID EQUATIONS: ( ORAL DOSING, PLASMA)
(EQ 5-18)
(EQ 5-19)
(EQ 5-20)
(EQ 5-21)
(EQ 5-22)
where = the comparative bioavailability
= the absolute bioavailabilty; the fraction of dose which ultimately reaches sys-
temic circulation (which is made up of the fraction of the dose which is absorbed
times the fraction which gets past the liver (first pass effect))
= absorption rate constant.
7.1.2 UTILIZATION
C
p
fD
V
d
------
k
a
k
a
K
--------------- e
Kt
e
k
a
t
( ) =
f
AUC oral ( ) Dose oral ( )
AUC iv ( ) Dose iv ( )
-------------------------------------------------------------- =
CB
AUC generic ( ) Dose generic ( )
AUC inovator ( ) Dose inovator ( )
-------------------------------------------------------------------------------------- =
t
p
k
a
K ( ) ln
k
a
K ( )
----------------------- =
X
a
v
------ K AUC
C
p
K AUC
t
+ ( ) =
CB
f
k
a
Oral Dosing
Ampicillin (Problem 5 - 17)
The following information is available for ampicillin: 90% is excreted unchanged and a 250 mg IV bolus dose yields an
AUC of 11 mic/mL*hr. The following blood level profile has been reported for two brands of ampicillin which were
given as 500 mg oral capsules.
Find the following:.
a. k for both products.
b. for both products.
c. for both products.
d. AUC for both products.
e. for both products.
f. for both products.
g.
h.
i for a 250 mg IV dose.
j.
k. Are these two products bioequivalent? Why or why not?
l. What infusion rate would be necessary to maintain a serum
TABLE 4-7
Time (hr)
MEAN SERUM LEVEL
LEDERLE BRISTOL
0.5 0.37 0.38
1.0 1.97 1.91
1.5 2.83 2.49
2.0 3.15 3.11
3.0 2.73 2.79
4.0 1.86 1.95
6.0 0.43 0.49
g
mL
--------
k
a
k
u
f
t
max
Cl
V
d
Cp
0
Cp
max
Oral Dosing
plasma concentration of 2mcg/mL
The data was plotted as above with the best fit line drawn. From the graph the fol-
lowing parameters were derived:
2) In a clinical study (DiSanto & DeSante, JPS 64:100,1975) prednisone was
administered to 22 adult healthy volunteres (average weight 64.5 kg) either as one
50 mg tablet (product A) or as ten 5 mg tablets (product B). The following data
was observed:
Time (hours) Concentration (mic/100ml plasma)
A B
TABLE 4-8 Comparison of Ampicillin
Lederle Bristol Ratio (L/B)

0.688 0.635

0.858 0.831

1.74 1.8 0.97

3 2.9 1.03
AUC (trapaziodal) 11.4 11.6 0.98
K hr
1
( )
K
a
hr
1
( )
T
max
hr ( )
C
p
( )
max
g mL ( )
Oral Dosing
0.5 40.8 57.3
1 70.0 77.1
2 79.5 82.3
3 80.7 69.4
4 68.6 60.6
6 49.4 48.0
8 35.0 33.7
12 15.3 17.4
24 2.1 3.0
Find ka's for both products.
Calculate peak time and Cp max and AUC for both products.
Can you conclude that these products are bioequivalent ?
(Reasons should include discussion of rate and extent of absorption)
Answer:
Oral Dosing
Product A Product B Ratio (A/B)
Ka (hr^-1) 1.19 1.8
Tmax (hr) 2 1.52 1.31
Cmax (mcg/100mL)83.2 82.8 1.00
AUC (trapazoidal)676.52 688.81 0.976
Can you conclude that these products are bioequivalent ?
No, Time to peak (Tmax) is outside guidelines.
3) Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthy
volunteers in a four way crossover design of four dosage forms containing 300 mg
of cimetadine. The following data was obtained:
Oral Dosing
A B C D
A.U.C. (mic/ml x hr)------ 5.2 5.4
% recovered in urine intact77.177.147.149.0
Peak serum conc.(mic/ml)------ 1.53 1.44
Onset (hr) 0 0.34 0.65
Duration (hr) 4.5 4.0 4.2 4.4
Time to peak (hr)0 1.0 2.0

A = IV bolus B = IM inj. C = Oral Liq. D = Oral Tab.
The plasma concentration - time profile for product A is as follows:
time(hrs) (ug/ml) time(hrs) (ug/ml)
1 1.79 6 0.45
2 1.36 12 0.08
4 0.78
a} Using linear regression, find K & Cp0.
b} What is the absolute bioavailability (f) of the liquid.
c} How does that correlate with % recovered intact in the urine?
d} Would you consider the oral forms bioequivalent?
Why/Why not?
Oral Dosing
f} What infusion rate would you suggest to maintain a plasma concentration of
0.75 mic/ml ?
g} How long would it take that infusion rate to attain a therapeutic plasma con-
centration of 0.5 mic/ml ?
Answer:
IV Bolus Parameters:
Cp max2.4 mic/mL
AUC 8.5
K 0.283 hr^-1
Oral Dosing
a} Using linear regression, find K & Cp0. (graph)
5/2/8.5 = 0.61
Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that to
show up in the urine because only 77% of the IV dose shows up in the urine
(.61*.77=.47).
d} Would you consider the oral forms bioequivalent? (No)
Why/Why not? Ratio of peak times ouside guidelines.
e} What infusion rate would you suggest to maintain a plasma concentration of
0.75 mic/ml ?
Q = Cpss * K * V = 0.75 mg/L * 0.283 hr^-1 * 125 L = 26.54 mg/hr

f} How long would it take that infusion to attain a therapeutic plasma concentra-
tion of 0.5 mic/ml ?
Cp = Q/(K*V)(1-exp(-K*T) = 0.5 = 26.54/(0.283*125)*(1-exp(-0.283*T)) --> 3.9
hr
4) LYSERGIC ACID DIETHYLAMIDE (LSD) was given to human volunteers at
the dose of 150 mic orally. (Impregnated blotter dosage form.) The following data
was obtained:
Oral Dosing
Time Cp (ng/ml) Time Cp (ng/ml)
0.25 1.75 2.0 4.6
0.5 2.9 3.0 4.1
0.75 3.7 4.0 3.3
1.0 4.2 6.0 2.1
1.5 4.6 8.0 1.4
a) Find ka
b) An IV dose of 100 mic resulted in an AUC of 20.4 ng/ml*hr. Find f.
c) The volunteers ability to concentrate as measured by their ability to do standard
tasks was also monitored. (100% control means no drug interference.) The fol-
lowing data was obtained:
Cp (ng/ml) % Control Cp (ng/ml) % Control
5.5 33 1.5 65
4.1 40 1.1 80
2.9 52
If 100 mic dose were given by IV bolus, how long would it be before the volunteer
would regain 80% of his control?
Answwer:
Oral Dosing
Evaluation of the graph of Concentration vs. time yields:
Cpmax 4.63 ng/mL
T max 1.7 hr
AUC (trap)30.07
K 0.225 hr^-1
Oral Dosing
m (-K) -0.225 hr^-1
Ka 1.22 hr^-1
f (AUCoral/Doseoral)/(AUCiv/Doseiv) = .98
Evaluation of the graph of response vs ln(concentration) yields:
dR/dln(c) = 27.86
Multiplying dR/dln(c) * dln(c)/dt (m of the previous graph) yields dR/dt = 27.86 *
-0.225 = 6.26%/hr
100 mic dose IV yields Cp0 of (Cp0 =AUC * K = 20.4 * 0.225) 4.59ng/mL.
The response of a 100 mic dose is (R = 27.86*ln(4.59)+19.9) 62.3%
Response = Response at t=0 - dR/dt * t
20% = 62.3% - 6.26%/hr * t hours
T = 6.76 hours
5. The following data was collected from a double blind cross over study between
500 mg dose of cloxacillin made by Bristol (Tegopen@) and a generic product
which you might want to put in your store.
Time (Conc. mic/ml) Time (Conc. mic/ml)
TEGOPEN GENERIC TEGOPEN GENERIC
Oral Dosing
0.25 .41 0.1 1.5 6.93 7.75
0.5 8.56 6.39 2 4.95 5.16
0.75 11.97 11.44 3 2.19 2.29
1 11.28 11.42 4 1.48 1.30
1.25 9.57 9.64
Calculate the comparative bioavailability.
Would you consider these products bioequivalent? Why/Why not?
Answer:
Oral Dosing
Evaluation of the above graphs yields:
Tegopen GenericRatio (G/T)
Cpmax (mic/mL)10.8 9.94 0.92
T max (hr) 0.74 0.89 1.20
AUC (trap) 21.7 21.06 0.97
K (hr^-1) 0.72 0.8
ka (hr^-1) 4.3 2.69

Actual evaluation of ka and peak time is dificult because of the pucity of data at
early time points however all relavent parameters meet guidlines.
7. The F.D.A. reported the following data submitted to be consideration regarding
the equivalence of Mylan Pharmaceuticals' Tetracycline with that of Lederle and
an intervenous bolus dose. (Dose 250 mg).
Time(hrs) Conc.(mcg/ml) Time(hrs) Conc.(mcg/ml)
Lederle Mylan I.V. Lederle Mylan I.V.
0.5 0.55 0.20 5.2 4 2.70 2.60 2.9
1 1.80 1.35 4.8 6 2.20 1.80 2.1
1.5 2.11 1.75 4.4 9 1.35 1.25 1.26
2 2.35 2.10 4.0 12 0.83 0.74 0.76
Oral Dosing
3 2.65 2.25 3.4 15 0.50 0.45 0.46
Would you consider Mylan to be bioequivalent to the Lederle product ?
Calculate the absolute bioavailability of Lederle Tetracycline.(.77)
f) Calculate the volume of distribution of tetracycline. (44.3 L)
g) Tetracycline has a pKa of 9.7. Tetracyclines tend to localize in the dentin and
enamel of developing teeth causing hypoplasia and permanent discoloration of
teeth. Would you recomend tetracyline for a 110 pound lactating mother ?
Support your argument with the dose of the child. (Child's weight 11 lbs. and he
eats 2 oz of milk every 2 hours. Mom's average plasma concentration is main-
tained at 3 mic/ml by taking 250 qid. pH of the milk is 6.1, pH of blood is 7.4)
Answer:
Oral Dosing
Pharmacokinetic parameters:
Lederle Mylan IV
Cpmax (mic/mL)2.75 2.42 5.65
Tmax (hr) 3.04 3.08 0
AUC 26.4 23.3 31.4
k (hr^-1) 0.165 0.161 0.167
Ka (hr^-1) 0.684 0.729
Ratio of bioequivalence parameters (Cpmax, Tmax and AUC) are all within guide-
lines. So, the would be considered bioequivalent.
Absolute bioavailability f (= (AUCoral/DOSEoral)/(AUCiv/DOSEiv) = (26.4/
250)/(31.4/250) is 0.84.
Oral Dosing
Volume of Distribution (Dose/Cp0 = 250 mg/ 5.65 mg/mL) is 44.2 L

The ratio of milk to blood is about 200.
r(m/b) = (10^(pKa-pH) + 1)milk / (10^(pKa-pH) + 1)blood
= (10^(9.7-6.1)+1)/(10^(7.4-6.1)+1) = 10^3.6/10^1.3 = 10^2.3 = 200
Dose the kid gets is mom's plasma concentration * Ratio(M/b) * volume of milk /
day = 3 mic/mL * 200 * 60cc * 12 feedings = 432 mg.day
Mom gets 1000 mg/day
Ratio of dose on a mg/kg basis (kid/mom) = (432/5)/1000/50) = 4.32 - Kid's get-
ting more than mom.
Fifty miligrams of ketameperidine was given by IV bolus. The following urinary
profile was obtained for the only metabolite N-methyl-ketameperidine:
Collection period (hr) Mean urinary excretion rate (mg/hr)
0.0 - 0.5 2.26
0.5 - 1.5 5.83
1.5 - 2.5 5.43
2.5 - 3.5 4.60
3.5 - 5.0 2.36
Oral Dosing
5.0 - 7.0 1.47
7.0 -10.0 0.96
10.0 -18.0 0.44
Calculate K, km and ku.
What Percent of ketameperidine was metabolized?
Answer:
With only one data point in the early time points, the larger rate constant is in ques-
tion. The terminal slope is assumed to be K. The AUC will yield the amount of
ketameperidine which was metabolized (dXmu/dt * t = Xmu).
K (hours^-1) 0.216
AUC (mg)30.3
30.3 mg showed up as metabolite = 60.6% of 50 mg dose.
km = 60.6% * K = 0.131 hours^-1
Oral Dosing
kr = K - km = 0.085 hours^-1
Aminophylline consists of THEOPHYLLINE (85% W/W) & Ethylene diamine
(15% W/W)
THEOPHYLLINE is the active compound measured in blood.
THEOPHYLLINE has a volume of distribution of 0.45 l/kg.
THEOPHYLLINE is 10% excreted unchanged and 90% metabolized to inactive
metabolites.
THEOPHYLLINE has a therapeutic range between 20 and 10 mg/l.
AUC FROM 0 to infinity for THEOPHYLLINE (given as 400 mg AMINPHYL-
LINE) is 120 mg/l x hr.
The average plasma concentration of THEOPHYLLINE given as 400 mg of AMI-
NOPHYLLINE is as follows:
time conc. time conc.
(hrs) (mg/L) (hrs) (mg/L)
0.5 7.24 4.0 8.06
1.0 9.56 6.0 6.89
2.0 10.00 8.0 5.57
3.0 8.84 10.0 4.53
Find f, K, ka, Vd,total body clearance.
Find the infusion rate necessary to maintain a plasma concentration of 15 mg/l.
Oral Dosing
Answer:
AUC (mg/L)*hr117.8
K (hr^-1) 0.096
ka (hr^-1) 2.11
f = (AUCoral/DOSEoral)/(AUCiv/DOSEiv) =
= (117.8 / 400 )/(120 / 400 ) = 0.98
Vd
AUC * K = Cp0iv
120 * 0.096 = 11.52 mg/L
Vd = Dose/Cp0 = (400mg*0.85)/11.52 = 29.5 L
TBC = K * Vd = 0.096/hr * 26.5L = 2.83 L/hr
Oral Dosing
Infusion rate = Q = Cpss * TBC = 15 mg/L * 2.83 L/hr = 42.45 mg/hr Theophyl-
line = 42.45/.85 = 50 mg/hr Aminophylline

Abbott labs has provided the following data conserning their ORETIC tablets
(hydrochlorthiazide tablets U.S.P.) Dose given was 50 mg.
(hrs) (mg/L) (hrs) (mg/L)
0.5 0.05 3.0 0.31
1.0 0.21 4.5 0.23
1.5 0.27 6.0 0.18
2.0 0.31 8.0 0.12
a Find K, ka, Cmax,
Answer:
Oral Dosing
The data is plotted both without (first figure) and with (second figure) a lag-time
which is associated with the release of the drug from the delivery system. Note
that the addition of the lag-time improves the fit.
The parameters obtained from each fit are:
WithoutWith
Cpmax (mg/L)0.22 0.31
Tmax (hr) 3.45 2.28
AUC (mg/L*hr)2.2 2.26
K (hr^-1) 0.216 0.201
ka (hr^-1) 0.380 1.10
t lag (hr) 0.0 0.393
Oral Dosing
It takes the tablet about 20 minutes to release the drug!

Wilkenstein et al.(Gastroenterology 74:360,1978) tested 12 normal healthy volun-
teers in a four way crossover design of four dosage forms containing 300 mg of
cimetadine. The following data was obtained: A B C D
AUC(mic/ml x hr) --- --- 5.2 5.4
recovered in urine intact77.177.1 54.9 55.8
Peak serum conc.(mic/ml)--- --- 1.53 1.44
Onset (hr) 0 0.34 0.65
Duration (hr) 4.5 4.6 4.2 4.4
Time to peak (hr) 0 1.0 2.0
A = IV Bolus B=IM injection C = Oral liquid D= Oral tablet
The plasma concentration vs. time profile for product A is as follows:
time (hrs) conc.(ug/ml)
1 1.79
2 1.36
4 0.78
6 0.45
12 0.08
a} find K, Cp0.
Both can be found from the graph. K = .283/hr Cp0 = 2.36 mic/ml
Oral Dosing
5.2/8.5 = 0.61
Very well. Only 61% (f) of liquid gets in and you would expect only 77% of that
to show up in the urine because only 77% of the IV dose shows up in the urine
(0.61 * .77 = .47).
d} How can you explain the variation in % recovered intact in the urine?
e} Would you consider the oral forms bioequivalent ? Why/Why not?
No. The ratio of peak times is outside the guidelines.
f} What infusion rate would you suggest to maintain a plasma concentration of
0.75 mic/ml?
Q = Cpss * K * V = 0.75 mg/L * 0.283/hr * 125L = 26.54 mg/hr
g} How long would it take that infusion rate to attain a therapeutic plasma concen-
tration of 0.5 mic/ml ?
Cp = Q/(K * V)(1-exp(-K*T) = 0.5 = 26.54/(0.283 *125)*(1-exp(-0.283 * T)) -
> 3.9 hr
Roxane labs of Columbus, Ohio offers the following data for your review of their
Quinidine Sulfate tablets (Dose 200 mg). It is compared against the reference
standard by Ely Lilly and company at the same dose.
Oral Dosing
Time (hours)Concentration (mcg/ml)
Roxane Lilly
1 .42 .58
2 .73 .77
3 .71 .74
4 .61 .66
6 .45 .52
8 .32 .34
12 .20 .22
a) Calculate the comparative bioavailability.
b) Would you consider Roxane Quinidine Sulfate to be bioequivalent to the Lilly
product ?
Answers
Oral Dosing
Oral Dosing
Roxane labsEli Lilly
w/o w w/o w Rw/o(R/L)Rw(R/L)
Cpmax (mcg/mL)0.650.740.740.76 0.88 0.97
AUC (mcg/mL*hr)6.086.236.756.84 0.90 0.91
Tmax (hr) 2.69 2.05 2.33 2.10 1.15 0.98
T lag (hr) 0.0 0.70 0.0 0.36
Yes. Ratios are within guidelines.
Shand et al. offers the following data for propranolol : Answers:
Time Concentration (ng/ml)
(hours) 10 mg I.V. 80 mg oral
0.5 -- 50
1 -- 77
1.5 -- 100
2 29 100
3 24 90
4 18 78
5 15 59
6 11 45
7 9 32
Oral Dosing
a) find ka
b) Calculate the absolute bioavailability of propranolol.
c) Calculate TBC
Oral Dosing
IV data Oral Data
w/o w
AUC (ng/mL*hr)201.3562.8 540
Cpmax (ng/mL) 47.7 97.8 99.7
Tmax (hr) 0 2.0 2.1
K (hr^-1) 0.239 0.324 0.421
ka (hr^-1) --- 0.715 0.548
T lag 0.0 0.02
Absolute bioabailability = (AUCoral/DOSEoral)/(AUCiv/DOSEiv)
= (562.8/80) /(201.3/10) = 0.35 or using lag time data
(540 / 80) /(210.3/10) = 0.335
TBC = Dose / AUC = 10,000 mic/ 201.3 mic/L*hr = 50 L/hr or
0.35*80,000mic /562.8 mic/L*hr = 50 L/hr
Niazi et al. offers the following data for meperadine :
Meperidine : is 95% metabolized
has an absolute bioavailability of 0.4
has a hepatic plasma extraction ratio of 0.6
has a volume of distribution of 100 L.
has a half life of 3.5 hours.
Oral Dosing
a) Calculate TBC
TBC = K * V = (0.198/hr)(100L) = 19.8 L/hr
b) Calculate the intrinsic hepatic plasma clearance of meperidine.
19.8 L/hr * .95 = 18.8 L/hr
c) Calculate the effect on total body clearance in a patient with viral hepititis (FI =
0.3).
Cl
h
*/Cl
h
= (.3)(1)/1 + .6(.3 - 1) = .3/.58 = .517
(.517)(18.8) = 9.72
TBC = 1 + 9.72 = 10.72
d) Calculate the effect on total body clearance in a patient with stenosis (FR = 0.3).
Cl
r
*/Cl
r
= (1)(.3)/.3 + .6(1 - .3) = .3/.72 = .417
TBC = 18.8 + .417 = 19.22
e) Comment on which patient might need modification in therapy and why.
The patient with viral hepatitis would need modification in therapy. Because
of the decrease in TBC, we can see that the drug is staying the body much
longer than normal, therefore the dosage regimen should be decreased.
Chlorthalidone is used to treat high blood pressure. The following information is
offered regarding a generic
and a brand name chlorthalidone 50 mg tablet:
Time Conc. (mcg/ml)
Oral Dosing
(hours) Hygroton@Generic
.5 0.14 0.15
1 0.51 0.64
2 1.23 1.67
3 1.94 2.48
4 2.20 2.91
6 2.64 3.49
8 2.86 3.52
12 3.43 3.82
24 3.22 3.38
48 2.45 2.74
72 1.53 1.91
96 1.20 1.40
120 0.76 0.77
Pharmacokinetic parameters
Cpmax (mg) 3.73 4.62
Time to peak (hr) 13.810.8
AUC (0 to Inf)293 336
Xu inf (mg)18.3 22.1
Ka (hr^-1)0.168 0.253
Ke (hr^-1)0.019 0.019
Oral Dosing
Average mean83.1 84.5
blood presure
a) Calculate the comparative bioavailability.
(336/50mg)/(293/50mg) = 1.15
b) Would you consider the generic product to be bioequivalent to the USV
(Hygroton@) product? Prepare a short statement that you would tell a patient
regarding why you would or would not make a generic substitution for this drug.
No. The maximum concentration the generic is too much greater than that of
the brand name product.
They are not considered to be bioequivalent.
R(G/H)
Cpmax (mg) 1.23 outside
Time to peak (hr)0.78outside
AUC (0 to inf)115 ok
Buspirone is a new anxiolytic agent that has been found to be effective for the
treatment of generalized anxiety disorder at a mean dose of approximately 20 mg/
day orally in divided doses. Buspirone is metabolized almost entirely. Less than
0.1% is found intact in the urine. The following data has been presented by Gam-
mans (Am J Med:80(supp 3b),41-51;1986):
Time (hours)Concentration (ng/ml)
(hours) 1 mg I.V.20 mg oral
Oral Dosing
0.25 -- 1.07
0.50 4.33 1.76
1.0 3.75 2.45
2 2.80 2.51
3 2.10 2.05
4 1.57 1.60
6 0.8 0.91
a) find ka
b) Find Oral Peak Time and Oral Cmax.
c) Calculate the absolute bioavailability of buspirone.
answer:
Oral Dosing
IV Oral
Cpmax (ng/mL) 5.0 2.6
AUC (0 to inf)17.4 13.9
Tmax (hr) 0 1.5
K (hr^-1) 0.290 0.289
ka (hr^-1) 1.3
Absolute bioavailability, f, = (AUCoral/DOSEoral)/(AUCiv/DOSEiv)
= ( 13.9 / 20) /( 17.4/ 1 )
= 0.04
Valproate is a carboxylic acid anticonvulsant. Its activity may be related, at least
in part, to increase concentrations of the neurotransmitter inhibitor gamma ami-
nobutyric acid in the brain. It is used alone or in combination with other anticon-
vulsants. in the prophylactic management of petit mal. It appears to be almost
entirely cleared by liver function with negligible amounts excreted into the urine
unchanged. It comes as soft gelatin capsules of 250 mg and enteric coated tablets
250 and 500 mg as well as oral syrup of 250 mg / 5 cc. Two different formula-
tions of Valproate (250 mg) were prepared by Abbott and compared. The data is as
follows:
Oral Dosing
Time(Hr.)Formulation BFormulation A
0.5 3.4 AUC = 287 mg/L * hr
1.0 6.0 Ka = 0.7 hr^-1
1.5 7.9 Ke = 0.065 hr^-1
2.0 9.3
2.5 10.3
3.0 10.9
4.0 11.6
6.0 11.4
8.0 10.5
12.0 8.3
18.0 5.7
24.0 3.8
1) find ka for formulation B.
2) Five hundred mg of valproate was administered by IV bolus. The AUC for that
route was 574 mg/L * hr. Calculate f for formulation A. Calculate Cp0 for the IV
dose.
3) Find Peak Time and Cmax for formulation A.
4) Calculate the comparative bioavailability of formulation B.
5) Would you consider formulation B to be bioequivalent to Formulation A ? Pre-
pare a short statement in which you would substantiate that stand that you might
Oral Dosing
need to respond to another health professional who asked you to stock that formu-
lation for his patients.
6) Calculate the Total Body Clearance (TBC) of valproate.
Answers:
Formulation B R(A/B)
AUC = 243.3 mg/L * hr 1.18
Cpmax = 11.7 mg/L1.12
Tp max = 4.70 hr0.79
ka = 0.493 hr^-1
K = 0.0655
Tmax(A) = ln(ka/K)/(ka-K)= 3.75 hr
cpmax =
(ka/(ka-k))*(fX0/Vd)*(exp(-k*tmax)-exp(-ka*tmax)
13.3 mg/L
Absolute bioavailability, f,=(AUCoral/DOSEoral)/(AUCiv/DOSEiv)
= (287/250)/(574/500)
= 1.0
Oral Dosing
Comparative bioavailability =(AUCb/DOSEb)/(AUCa/DOSEa) = 243.3/287 =
0.85
TBC = Dose / AUC = 500 mg / 574 mg /L * hr
The following data was made available by Lederle Labs regarding its generic
Procainamide HCl. (Dose 250mg).
Procainamide is a base (pka =9.1). As the hydrochloride salt it is 87% Procaina-
mide.
Time (hrs)Conc.(mcg/ml) Procainamide Base
Lederle Squibb I.V.
0.33 0.68 0.26
0.5 0.82 0.67
0.66 1.17 0.93
1 1.23 1.12 1.45
1.33 1.31 1.19 1.35
2 1.39 1.12 1.18
3 0.93 0.96 0.95
4 0.74 0.74 0.77
6 0.51 0.51 0.51
8 0.32 0.30 0.33
12 0.11 0.09 0.14
Oral Dosing
a) find ka of the Squibb product
b) ka of the Lederle product.
c) Calculate the comparative bioavailability.
d) Would you consider Lederle to be bioequivalent to the Squibb product ?
e) Calculate the absolute bioavailability of Lederle Procainamide.
f) Calculate the volume of distribution of procainamide.
g) Would you recommend your patient breast feed her newborn? Prepare a short
consult for her physician. Support your argument with the dose of the child.
(Child's weight 11 lbs. and he eats 2 oz of milk every 2 hours. Mom's average
plasma concentration is maintained at 4 mic/ml from a 1 g dose ever 6 hours. pH of
the milk is 6.3, pH of blood is 7.4)
Procainamide is cleared about 60% by liver and 40% by kidney function. 20 % of
cardiac output (70 ml/min/kg) goes to liver, 25% goes to the kidney. Mom's
weight is 130 lb. Assuming her plasma vs time profile to be similar to the Lederle
product (i.e. pharmacokinetic parameters obtained from this information can be
used):
h) Calculate Total body clearance
i) Calculate the intrinsic hepatic plasma clearance of procainamide.
j) Calculate the effect on her total body clearance if she were to contract viral hep-
atitis which effect liver function (FI = 0.4). Prepare a short consult for her physi-
cian as to whether you would recommend a change in therapy. d) Calculate the
effect on her total body clearance stenosis of the liver (FR = 0.4). Prepare a short
consult for her physician as to whether you would recommend a change in therapy.
Answers:
Oral Dosing
IV LederleSquibbR(L/S)
AUC (0 to inf)8.577.46.8 1.09
Cpmax 1.8 1.28 1.25 1.02
Tmax 0 1.43 1.45 0.99
K 0.212 0.247 0.256
ka --- 1.51 1.93
t lag 0 0 0.24
= 7.4 / 8.57
Oral Dosing
= 0.86
Vd = Dose/Cp0 = 0.87*250mg/1.8mg/L= 120.8 L
Ratio of milk to blood = (10^(9.1-6.3)+1)/(10^(9.1-7.4)+1)= 12.4
Kid's dose = 4 mic/mL * 12.4 * 60 mL/feeding * 12 feedings/day * 1 mg/1000 mic
= 36 mg/day
Ratio of kid's daily dose/# to Mother's daily dose/# = (36mg/11#)/(1000mg*4/
130#) = 0.42. The kid gets about half of the mother's dose!
Nifedipine (Procardia @) is a calcium channel blocker which specifically inhibits
potential-dependent channels not receptor-operated channels, preventing calcium
influx of cardiac and vascular smooth muscle (coronary, cerebral). Calcium
channel blockers reduce myocardial contractility and A-V node conduction by
reducing the slow inward calcium current. They are indicated in angina, cardiac
dysrhythmias, and hypertension among others. Nifedipine appears to be metabo-
lized entirely into an inactive metabolite, an acid and subsequently further metab-
olized to a lactone. Both the acid and the lactone are excreted into the urine and
the feces.
Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (Clin
Pcol Therap 1986; 40: 21-8) Reviewed the pharmacokinetics of Nifedipine. While
the drug is not routinely given by IV bolus and does not strictly conform to a one
compartment model, lets treat the data as if those problems can be ignored. The
following data is offered for evaluation:
25mg IV 10 mg oral tablet
Formula AFormula B
Time Cp Cp Cp
Oral Dosing
(hr.) (mic/l) (mic/l) (mic/l)
0.5 29.3 33.1
1 42.1 43.7
1.5 45.7 43.7
2 139 44.4 39.8
3 36.2 25.5
4 65.6 27 20.7
6 31.1 13.6 9.9
8 14.6 6.5 4.7
12 1.5 1.0
a} Find ka's of the two products.
b} Calculate peak time and Cp max for both products.
d} Can you conclude that these products are bioequivalent ? (you must support you
argument)
e) Calculate the absolute bioavailability of product A.
f} What infusion rate would you suggest to maintain a plasma concentration of 30
mic/L ?
Answers:
Oral Dosing
IV A B R(A/B)
Cpmax (mic/L)294.25 45.7 44.01.04
Tmax (hr) 0 1.57 1.18 1.33
AUC(0 to inf)785219.7182.7 1.20
ka (hr^-1)--- 1.0 1.6
K (hr^-1) 0.375 0.374 0.375
No,Tmax is outside the guidelines.
Oral Dosing
=(219.7/10)/(785/25)
=0.7
Q = Cpss * K * V = 0.955 mg/hr
Tetracycline HCl has a pKa of 9.7. Tetracyclines tend to localize in the dentin and
enamel of developing teeth causing hypoplasia and permanent discoloration of
teeth. Would you recommend tetracycline for a lactating mother ? Support your
argument with the dose of the child. (Child's weight 11 lbs. and he eats 2 oz of
milk every 2 hours. Mom's average plasma concentration is maintained at 4 mic/
ml she is taking 250 mg T.I.D. ( Milk pH = 6.1, Blood pH = 7.4)
T
m
/T
b
= 10
9.7 - 6.1
/10
9.7 - 7.4
= 20/1
The concentrarion of tetracycline in the mother's milk is 80 mic/ml
The child takes in 720 ml of milk per day
80 mic/ml * 720 ml = 57600 mic = 57.6 mg
57.6mg/5kg = 11.52mg/kg = dose that the child is getting from the mother's
milk.
I would not recomend tetracycline for a lactating mother. The dose that a nurs-
ing child gets from the milk too high.
Oxazepam (acid, pKa 11.5) is an anxyolytic sedative with the usual adult dose 10
mg 3 times daily. If the circulating plasma concentration of oxazapam were 20
Oral Dosing
mic/ml for nursing 120 lb mother, would her 9 lb infant be getting a comparable
mg per kg daily dose if he consumes 2 oz of his mothers milk every 2 hours. Pre-
pare a short consult for her physician in which you might (or might not) recom-
mend the patient stop breast feeding while she is on this medication. Include
appropriate calculations.
O
m
/O
b
= 10
11.5 - 6.1
/10
11.5 - 7.4
= 20/1
The concentration of the mother's milk would then be 400 mic/ml
400 mic/ml * 720 ml = 288000 mic given to baby = 288mg
288mg / 4.1kg = 70 mg/kg = dose/kg given to baby
This dose is much greater then that given to the mother. The mother should
discontinue breast feeding while taking Oxazepam.
Bioequivalence studies are sometimes done within the same company to check if
the tablets of the same drug, but different strengths (with the strength normalized)
could be considered equivalent (i.e. could two 5 mg tablets be considered equal to
one 10 mg tablet). While not strictly kosher (products are not pharmaceutical
equivalents because of different strengths), it is done. Here is the results of such a
study in which Zomax 100 and 200 mg tablets were compared. (Yes, I know that
Zomax was removed from the market after a short life of only 6 months.)
Zomax 100 mg tablet 200 mg tablet 50 mg IV bolus
Time Conc AUC Conc AUC Conc.
(hr) (mg/L) (0->t) (mg/L) (0->t) (mg/L)
0.25 1.41 0.18 4.03 0.50
0.5 1.98 0.60 5.13 1.65
0.75 2.15 1.12 5.18 2.94
1 2.12 1.65 4.89 4.20 1.14
Oral Dosing
2 1.56 3.49 3.37 8.33 0.764
3 1.05 4.80 2.26 11.14 0.512
4 0.707 5.67 1.51 13.03 0.343
6 0.318 6.70 0.68 15.22 0.154
8 0.143 7.16 0.306 16.20 0.069
1) What is the elimination rate constant for zomax (hr) ?
A) 0.2 B) 0.3 *C) 0.4 D) 0.5 E) 0.6
2) What is the volume of distribution of zomax given by IV bolus (L) ?
A) 43.85 B) 33.3 *C) 29.4 D) 25.9 E) 0.034
AUC = D/(Vd * K)
Vd = D/(AUC * K)
= 50mg/(4.25 * 0.4)
= 29.4 L
3) What is the volume of distribution of zomax given by 100 mg oral tablet ?
A) 43.85 *B) 33.3 C) 29.4 D) 25.9 E) 0.034
Vd = 100mg/(7.48 * 0.4)
= 33.4 L
Oral Dosing
4) What is the AUC(0->infinity_ for the IV bolus dose ?
A) 2.68 B) 2.85 C) 3.55 D) 4.08 *E) 4.25
5) What is the AUC(0->infinity) for the 100 mg tablet ?
A) 7.16 *B) 7.5 C) 16.20 D) 17 E) 37.38
6) What is the absolute bioavailability of the 100 mg tablet ?
A) 0.84 *B) 0.88 C) 1 D) 1.14 E) 1.19
(7.48/100)/(4.25/50) = 0.88
7) What is the AUC(0->infinity) for the 200 mg tablet ?
A) 7.16 B) 7.5 C) 16.20 *D) 17 E) 73.98
8) What is the absolute bioavailability of the 200 mg tablet ?
A) 0.84 B) 0.88 *C) 1 D) 1.14 E) 1.19
(16.9/200)/(4.25/50) = 1
9) What is K * AUC (0->infinity) for the 100 mg tablet (mic/ml) ?
A) 2.9 *B) 3.0 C) 6.5 D) 6.8 E) 14.95
7.48 * 0.4 = 2.99
Oral Dosing
10) What is the absorption rate constant for the 100 mg tablet ?
A) 1.7 B) 2.2 *C) 2.6 D) 3.2 E) 3.7
11) What is the intercept of the extrapolated line for the 200 mg tablet ?
A) 3.5 B) 4.1 C) 5.6 D) 6.1 *E) 7.6
12) What is the absorption rate constant for the 200 mg tablet ?
A) 1.7 B) 2.2 C) 2.6 D) 3.2 *E) 4.01
13) What is the Tmax for the 100 mg tablet ?
A) 0.5 B) 0.67 C) 0.75 *D) 0.85 E) 0.95
14) What is the Tmax for the 200 mg tablet ?
A) 0.5 *B) 0.67 C) 0.75 D) 0.85 E) 0.95
15) Would you consider these two tablets bioequivalent (given normalization for
dose) (consider all ratios to be the 100 mg / 200 mg parameter normalized as to
dose where applicable)?
A) Yes
B) No, because the ratio of the ka's is 0.70
C) No, because the ratio of the AUCs is 0.44
Oral Dosing
D) No, because the ratio of the Cmaxs is 0.41
*E) No, because the ratio of the Tmaxs is 1.27
16) What infusion rate would you recommend to maintain an average plasma con-
centration of 1 mic/ml ?
A) 17.5 B) 13.3 *C) 11.8 D) 10.4 E) 9.0
Vd = D/Cp0 = 50mg/1.7mg/L = 29.4
Q = Cpss * K * V = 1mg/L * 0.4/hr * 29.4L = 11.8
17) What would be the concentration (mg/L) 2 hrs after discontinuing the infu-
sion assuming you reached steady state ?
A) 0.67 B) 0.55 *C) 0.45 D) 0.37 E) 0.30
Cpss = Cp0 * e
-Kt
= 1mg/L * e
(-0.4 * 2)
= 0.44
A 110 pound mother breast feeds her 11 pound infant while on morphine sulfate
(base, pKa = 9.85). Mother's average circulating plasma levels are 0.5 ug/ml fol-
lowing a 10 mg IV dose q4h. (pH Milk = 6.1, pH blood = 7.4)
18) What is the Ratio of morphine concentration in the milk as compared to the
blood ?
A) 0.05 B) 0.5 C) 1 D) 2 *E) 20
Oral Dosing
Mm/Mb = 10
(9.85 - 6.1)
/10
(9.85 - 7.4)
= 20
19) How much (mg) morphine is contained in 120 cc of breast milk (the child con-
sumes 2 ounces every 2 hours) *A) 1.2 B) 0.12 C) 0.06 D) 0.03 E) 0.003
Mother's blood conc. is 0.5mic/ml therefore her milk conc. is 10 mic/ml.
10mg/L * 0.12L = 1.2 mg
20) In your professional judgment, will the child's dose cause a problem ?
A) No, morphine does not concentrate in the milk and thus the milk is ok to drink.
B) No, the dose is too small. The ratio of the child's dose to the mother's dose is
0.12.
C) Yes, even though the dose is small, we don't want any drug to get to the child.
*D) Yes, the dose is comparable to the mother's dose. The ratio of the child's to the
mother's dose is 1.2.
E) Not my job. I only give what the doctor orders.
Answers:
Oral Dosing
IV Tablet Tablet
50 mg 100 mg200 mgR(100/200)
AUC(0 to inf)4.257.4816.9 0.89
Cpmax 1.7 2.15 5.23 0.82
Tmax 0 0.82 0.64 1.28
K 0.4 0.4 -.4
ka --- 2.76 4.01
Tmax ratio is ouside guidelines.
Oral Dosing
Answers are rounded off. When you pick a foil, use that number in subsequent cal-
culations when needed.
Rifampin (unionized free base pKa 7.9) is a drug used to treat TB. The following
data was collected following a 600 mg oral tablet from the inovator (Treatment A),
and a 600 mg oral tablet from a generic (treatment B), and a 400 mg IV dose
(Treatment C).
Concentration (mic/mL)AUC(0->t)
TreatmentA B C B
Time (hours)
0.5 5.3 4.8 1.2
1 10.3 8.6 7.8 4.55
1.5 10.2 9.8 9.15
2 9.4 9.8 6.1 14.05
2.5 8.9 9.2 18.8
3 7.5 8.4 4.7
4 5.9 6.7 3.7
6 3.6 4.1 2.2
8 2.2 2.5 1.3
10 1.3 1.5 0.8
12 0.8 0.92 0.5
AUC(0->inf)53.957.7
Oral Dosing
(mic/mL*hr)
Lag time (min)18.610.5
Cp max10.6 9.9
Ka (hr^-1)2.66
1) What is the Cp0 for C (mg/L)? a) 0 b) 7.8 *c) 10 d) 12 e) 15
Cp0 = AUC * K
= 39.8 * 0.25
= 9.95
2) What is the volume of distribution of Rifampin (L)? a) 60 b) 51.3 *c) 40
d) 33.3 e) 26.7
Vd = D/Cp0
= 400mg/(9.95mg/L)
= 40.2 L
3) What is the half life for rifampin (hr)? *a) 2.8 b) 2.3 c) 2.0 d) 1.75 e)
1.5
t
1/2
= .693/0.25
= 2.77
Oral Dosing
4) What is the elimination rate constant for rifampin (hr^-1)? *a) 0.25 b) 0.3 c)
0.35 d) 0.4 e) 0.45
5) Calculate the AUC (0->1hr) for C (mic/mL*hr). a) 1.95 *b) 3.9 c) 7.8 b)
8.9 e) 17.8
6) Calculate the AUC (12hr->inf.) for C (mic/mL*hr). *a) 2 b) 1.67 c) 1.43
d) 1.25 e) 1.11
0.5/0.25 = 2
7) Calculate the AUC (0->inf) for C (mic/mL*hr). a) 16 b) 26.85 c) 35 *d)
40 e) 60
8) Calculate the absolute bioavailability for the generic product. a) 0.70 *b)
0.95 c) 1 d) 1.05 e) 1.43
(57.7/600)/(39.8/400) = 0.966
9) Calulate the comparative bioavailability for the generic product. a) 0.70 b)
0.95 c) 1 *d) 1.05
e) 1.43

(57.7/600)/(53.9/600) = 1.07
10) Using Wagner-Nelson method, calculate the Ka for the generic product (hr^-
1). a) 0.45 b) 1 c) 1.55 d) 2 e) 2.45
Oral Dosing
11) Calculate the peak time for the generic product (min). a) 37 b) 67 c) 86 d)
91 e) 105
tp = [ln(Ka/K)]/(Ka - K)
= [ln(1.37/0.25)]/(1.37 - 0.25)
= 1.52 hr = 91 min
12) Calculate the peak time for the brand name product (min). a) 37 *b) 59 c)
86 d) 95 e) 105
tp = [ln(2.66/0.25)]/(2.66 - 0.25)
= 0.98 hr = 59 min
13) Are the two products bioequivalent?
a) yes, all federal requirements are met.
*b) no, the ratio of the peak times are out side federal requirements.
c) no, the ratio of the lag times are out side federal requirements.
d) no, the ratio of the Kas are out side federal requirements.
e) no, the ratio of the comparative bioavailabilities are out side federal require-
ments.
14) What is the ratio of the concentration of milk (pH 6.1) to blood (pH 7.4)? a)
0.05 b) 0.05 c) 1 d) 15.4 *e) 20
R
m
/R
m
= 10
(7.9 - 6.1)
/10
(7.9 - 7.4)
Oral Dosing
= 20
15) The average plasma concentration for the mother (110#) is 2.5 mg/L from a
600 mg once a day dosing regimen. If the baby (11#) drinks 780 mL of milk a day
(2 - 2.5 ounces every 2 hours), what is his daily dose (mg)?
a) 0.1 b) 0.13 c) 2 d) 30 *e) 39
Mother's blood average blood conc. is 2.5 mg/L therefore her milk conc. is 50
mg/L.
If the baby drinks 780 ml of milk he/she will get 39 mg of the drug.
16) Would you recommend mom stop breast feeding? (What % of the mom's daily
dose (mg/kg) is the baby's daily dose (mg/kg)?)
a) No, the child's dose is less than 1% of the mother's dose on a mg/kg/day basis.
b) No, the child's dose is about 5% of the mother's dose on a mg/kg/day basis.
c) Maybe, the child's dose is about 10% of the mother's dose on a mg/kg/day basis.
*d) Yes, the child's dose is about 50% of the mother's dose on a mg/kg/day basis.
e) Yes, the child's dose is about the same as the mother's dose on a mg/kg/day
basis.
17) While Rifampin is not administered by IV infusion, what would be the infu-
sion rate necessary to maintain an average plasma concentration of 2.5 mg/L (mg/
hr)? *a) 25 b) 50 c) 100 d) 150 e) 200
Vd = D/Cp0
= 400/10.02
= 39.9 L
Oral Dosing
Q = Cpss * K * Vd
= 2.5 * 0.25 * 39.9
= 25 mg/hr
18) While Rifampin is not administered by IV bolus, what would be the loading
dose necessary to obtain a plasma concentration of 2.5 mg/L (mg)? a) 25 b) 50
*c) 100 d) 150 e) 200
Loading Dose = Cpss * Vd
= 2.5 * 39.9
= 100mg
19) While Rifampin is not administered by IV infusion, what would be the infu-
sion rate necessary to obtain a plasma concentration of 2.5 mg/L in about 2.5 to 3
hours (mg/hr)? a) 25 *b) 50 c) 100 d) 150 e) 200
Cp = [Q/(K * Vd)] * (1 - e
-kt
)
Q = (Cp * K * Vd)/(1 - e
-kt
)
= (2.5mg/L * 0.25 * 39.9L)/[1 - e
(-0.25 * 2.75)
]
= 50 mg/hr
20) Rifampin is a semisynthetic derivative of rifamycin B, an antibiotic derived
from Streptomyces mediterranei. The minimum inhibitory concentration for N.
menengitidis is 0.1 - 1 mic/mL. It is distributed well into bodily fluids. About 30%
shows up in the urine as free drug and active metabolite while 60% shows up in the
feces as metabolite. The secretary is hounding me to finish the exam, so the
answer to 20 is a. Also, rifampin is 85% protien bound at physiological concen-
trations. *a) 25 b) 50 c) 100 d) 150 e) 200
Answers:
Oral Dosing
A B IV
Tmax 1.27 1.7 0
K 0.25 0.25 0.25
ka 2.66 1.37 ---
AUC 53.9 57.7 39.8
Oral Dosing
Cpmax 10.6 9.9 10.02
PHARMACOKINETICS SECOND HOUR PRACTICE EXAM #2
(1) Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:
a}Cpss b}feathering c}Wagner-Nelson method d}clearance e}f
(2) For each of the following pairs of variables (ordinate against abscissa), draw
a graph illustrating the qualitative profile of their relationship. Where appropri-
ate, indicate the nature of important slopes, intercepts, and values. Unless your
specifically indicate on your plot that semi-log paper is being considered (write "S-
L"), it will be assumed that rectilinear paper is being considered. Graphs are for a
drug given by oral route where applicable.
Oral Dosing
a} total amount of drug collected minus the amount collected at the time in the
urine vs time
b} Plasma concentration of a drug given by oral route vs time
c} Plasma concentration of metabolite of a drug given by IV bolus vs time
d} Steady state plasma concentration vs infusion rate
e} Steaty state plasma consentration vs clearance
SECTION I

(1) Succinctly define, stating rigorously the meaning of any symbols used and the
dimensions of measurement:)
a}Cpss b}f c}Absolute Bioavailability d}Comparative Bioavailability
(2) Compare and contrast:a}Wagner-Nelson and feathering methods b} Treat-
ment of plasma and urine data using Wagner-Nelson
(3) For each of the following pairs of variables (ordinate against abscissa), draw
a graph illustrating the qualitative profile of their relationship. Where appropri-
ate, indicate the nature of important slopes, intercepts, and values. Unless your
specifically indicate on your plot that semi-log paper is being considered (write "S-
L"), it will be assumed that rectilinear paper is being considered. Graphs are for a
drug given by oral route where applicable.
dXu/dt vs t for a drug given orally.
Oral Dosing
dXmu/dt vs t for a drug given by IV bolus.
Steady state plasma concentration vs infusion rate
Steady state plasma concentration vs elimination rate constant
SECTION I
1. Succinctly define, stating rigorously the meaning of any symbols used and the
a) clearance b)f c) absolute bioavailability d) comparative bioavailability e)
AUC
2. By means of an annotated phase diagram explain how freeze-dried pharmaceuti-
cal injectables are made.
3. For each of the following pairs of variables (ordinate against abscissa) draw a
graph illustrating the qualitative profile of their relationship. Where appropriate,
indicate the nature of important slopes, intercepts, and values. Unless you specifi-
cally indicate on your plot that semi-log paper is being considered (write "SL"), it
will be assumed that rectilinear paper is being considered.
Pharmacological Response vs time
Peak time vs ka for oral dose
Fractional change in total body clearance vs. renal clearance
Oral Dosing
AUC vs ka
AUC vs ke
SECTION I
a) first pass effect b) f c) Intrinsic clearance
d) comparative bioavailability e) Extraction ratio
2. By means of an annotated phase diagram explain how a metastable polymorph
can be formed and how these polymorphs might effect the bioavailability of the
drug.
indicate the nature of important slopes, intercepts, and values. Unless your specif-
ically indicate on your plot that semi-log paper is being considered (write "S-L"),
it will be assumed that rectilinear paper is being considered
fractional change in total body clearance vs plasma flow for drugs having a large
extraction ratio.
Peak time vs ka for oral dose
Fractional change in total body clearance vs. hepatic clearance.
AUC vs ka
Oral Dosing
AUC vs clearance
SECTION I
Henderson-Hasselbach relationship
Therapeutic alternatives
Therapeutic equivalents
comparative bioavailability
Extraction ratio
Briefly discuss generic substitution by the pharmacist. Include such topics as when
it might be admissable and the liabilities involved.
indicate the nature of important slopes, intercepts, and values. Unless you specif-
a) fractional change in total body clearance vs fractional change in plasma
flow for drugs having a small extraction ratio.
Oral Dosing
b) Peak time vs dose for oral dose
c) Fractional change in total body clearance vs. fractional change in hepatic
clearance for drugs having a large extration ratio.
d) Ratio of milk to blood for basic drugs vs pKa.
e) Ratio of milk to blood for acidic drugs vs pKa.
SECTION I
a) Bioequivalance
b) Intrinsic Clearance
c) first pass effect
d) Henderson - Hasselbach equation
e) f
2.Compare and contrast absolute and relative bioavailability.
3.For each of the following pairs of variables (ordinate against abscissa) draw a
indicate the nature of important slopes, intercepts, and values. Unless you specif-
Oral Dosing
a) Cpmax vs f for a drug given orally.
b) Cpmax vs dose for a drug given orally.
c) Cpmax vs Vd for a drug given orally.
d) TBC vs Fi(H) for a drug with a high extraction ratio in the liver.
e) TBC vs Fr(H) for a drug with a high extraction ratio in the liver
SECTION I
a) Henderson-Hasselbach relationship
b) Therapeutic alternatives
c) Therapeutic equivalents
d) Comparative bioavailability
e) Extraction ratio
2. Briefly discuss generic substitution by the pharmacist. Include such topics as
when it might be admissible and the liabilities involved.
indicate the nature of important slopes, intercepts, and values. Unless you specifi-
cally indicate on your plot that semi-log paper is being considered (write "SL"), it
will be assumed that rectilinear paper is being considered
a) fractional change in total body clearance vs fractional change in plasma
flow for drugs having a small extraction ratio.
Oral Dosing
b) Peak time vs dose for oral dose.
c) Fractional change in total body clearance vs. fractional change in intrinsic
hepatic clearance for drugs having a large extraction ratio.
d) Ratio of blood to milk concentrations for basic drugs vs pKa.
e) Ratio of blood to milk concentrations for acidic drugs vs pKa.
PHARMACOKINETICS SECOND HOUR PRACTICE EXAM # 10
SECTION I
a) Henderson-Hasselbach relationship
b) Therapeutic alternatives
c) Therapeutic equivalents
d) Comparative bioavailability
e) Absolute bioavailability
f) Bioequivalents
2. Compare and Contrast: Feathering and Wagner-Nelson method.
3. For each of the following pairs of variables (ordinate against abscissa), draw a
indicate the nature of important slopes, intercepts, and values. Unless you indicate
on your plot that semi-log paper is being considered (write SL), it will be assumed
that rectilinear paper is being considered. Graphs are for a drug given by an oral
delivery system where applicable.
a) Cpss vs. K
b) Cp vs. ka
Oral Dosing
c) Ratio of Milk to Blood for acidic drugs vs. pKa
Pharmacokinetics practice exam #11
Pharmaceutical alternatives may have different:
I. therapeutic moieties
II. dosage forms or strengths
III. salt or ester forms of the same therapeutic moiety

2) Pharmaceutical equivalents must have the same:
I. active ingredients and strength
II. dosage form and route of administration
III. rate and extent of absorption
3) Bioequivalent drug products must have the same:
I. active ingredients and strength
II. dosage form and route of administration
III. rate and extent of absorption
4) Therapeutic equivalents are:
Oral Dosing
I. pharmaceutical alternatives
II. pharmaceutical equivalents
III. bioequivalents
5) The Wagner-Nelson method
I. uses curve stripping or feathering techniques
II. can be used to find ku and km
III. uses AUC calculations
6) The Federal guidelines for for bioequivalence require that the following phar-
macokinetic parameters be within + 20 % of
the innovator's product:
I. AUC, Peak time, Cpmax
II. Ka, Ke
III. Vd
7) The steady state plasma concentration of a drug given by intravenous infusion is
dependent on:
I. length of time of of infusion
II. volume of distribution
III. elimination rate constant, K.
8) The peak time of a drug given by the oral route is dependent on:
Oral Dosing
I. the absorption rate constant
II. the metabolism rate constant
III. the excretion rate constant
9) The slope of the terminal portion of the graph of the metabolite of a drug which
(the drug, not the metabolite) was given
by intravenous bolus injection could be:
I. - the elimination rate constant of the metabolite
II. - the elimination rate constant of the drug
III. - the absorption rate constant of the metabolite
10) Comparative bioavailability includes calculations of the ratio(s) of the fol-
lowing pharmacokinetic parameters of two
oral products (generic / Innovator) normalized for dose :
I. AUC (0 to Inf)
II. Peak time
III. Cpmax
Pharmacokinetics practice second hour exam #12
Oral Dosing
Where the are only three foils (possible quesses), please use K type system:
(NOTE: if foils are equivalent, all must be selected)
A) I ONLY
B) III ONLY
C) I AND II ONLY
D) II AND III ONLY
E) I, II, AND III
1) Steady state plasma concentration obtained by continuous infusion is inversely
proportional to:
I Infusion rate
II elimination rate constant
III volume of distribution
2) Steady state plasma concentration obtained by continuous infusion is directly
proportional to:
I Infusion rate
II time
III volume of distribution
3) When calculating the AUC for an oral product using the trapezoidal rule, con-
centrations necessary to calculate the
first trapezoid are:
Oral Dosing
I the intercept of the extrapolated line of the plasma vs. time profile.
II the concentration at time zero, Cp0
III the concentration at the first time point
4) When calculating the AUC for an IV product using the trapezoidal rule, con-
centrations necessary to calculate the
first trapezoid are:
I the intercept of the extrapolated line of the plasma vs. time profile.
II the concentration at time zero, Cp0
III the concentration at the first time point
5) Absolute bioavailability is a calculation which
I must be between .80 and 1.20
II compares an oral product to an IV bolus dose.
III is the ratio of the normalized AUCs of the products tested.
6) Comparative bioavailability is a calculation which
I is the ratio of the normalized AUCs of the products tested.
II must be between .80 and 1.20
III compares an oral product to an IV bolus dose.
7) When plotting the Wagner-Nelson function vs. time, a plot which proceeds hor-
izontally for a measurable time and then
declines:
Oral Dosing
I is because of poor data in the early part of the data set.
II only the declining portion should be used to calculate ka.
III is an indication of a delay in release of the drug from the delivery system, a lag
time.
8) When considering ion trapping, comparing a drug which forms sulfate salts
distributing between mother's milk and
blood, the ratio of total drug in milk to total drug in blood (Rm/b) can be
I greater than one.
II one.
III less than one.

9) When considering ion trapping, comparing a drug which forms sodium salts
distributing between mother's milk and
blood, the ratio of total drug in milk to total drug in blood (Rm/b) can be
I greater than one.
II one.
III less than one.

10) When using dry starch as a tablet disintegrating agent,
I tablet hardness is directly proportional to starch content.
II starch acts by allowing the water to wick into the tablet.
III a threshold minimum amount of starch is necessary before any disintegration
action is apparent.
Oral Dosing
Cyclosporine A (Problem 8 - 6)
Quigano, R., et al., "Effect of atropine of gastrointestinal motility and the bioavailability of cyclosporine A in rats", Drug Metabo-
lism and Disposition, Vol. 21, No. 1, (1993), p. 141 - 143.
In this study rats with an average weight of 300 g were given either an IV bolus dose of cyclosporine A (CyA)
or an oral dose of CyA. Subsequently, doses of atropine were given; however, the data below is that which was gath-
ered prior to atropine administration. A summary of the some of data obtained from this experiment is given below.
From the preceding data, please calculate the following:
1.
2. , the elimination rate constant
3.
Parameter IV Oral Solution Brand Tablet Generic Tablet Bioequivalence
Dose (mg/kg)
AUC
AUMC
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
Relative Bioavailability
Generic Equivalent (Yes / No)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
MRT
iv
k
e
t
1 2
Oral Dosing
4.
5.
6. The plasma concentration ( ) of cyclosporine A at 1 hour after the iv dose was given.
7. hour for the iv dose
8. , the absolute bioavailability of oral cyclosporine A.
9 .
10.
11. , the apparent absorption rate constant.
12. for the oral dose.
13. , the maximum concentration of the oral dosage form given as a single dose.
Cp
0
V
d
Cp
AUC
0 1
f
MRT
oral
MAT
oral
k
a
t
peak
Cp
max
Oral Dosing
Fosinopril (Problem 8 - 7)
Gehr, T., et al., "The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients", European Journal of Clin-
ical Pharmacology, Vol. 45, No. 5, (1993), p. 431 - 436.
Fosinopril (MW 562.6) is a new Angiotension Converting Enzyme (ACE) Inhibitor used in the treatment of
hypertension. Following oral administration, fosinopril is rapidly and almost completely hydrolyzed to its pharmaco-
logically active metabolite, fosinoprilate (MW 435.2). About 50% of the drug is excreted unchanged through the kid-
neys. In this study, patients received either 7.5 mg of fosinoprilat administered intravenously or 10 mg of fosinopril
administered orally. A summary of the some of data obtained from this experiment is given below.
1.
Dose (mg/kg)
AUC
AUMC
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
MRT
iv
k
e
Oral Dosing
3.
4.
5.
6. The plasma concentration ( ) of fosinopril at 1 hour after the iv dose was given.
8. , the absolute bioavailability of oral fosinopril.
9 .
10.
t
1 2
Cp
0
V
d
Cp
AUC
0 1
f
MRT
oral
MAT
oral
k
a
t
peak
Cp
max
Oral Dosing
Verapamil (Problem 8 - 8)
Rutledge, D., Pieper, J., and Mirvis, D., "Effects of chronic phenobarbital on verapamil disposition in humans", The Journal of
Pharmacology and Experimental Therapeutics, Vol. 246, No. 1, (1988), p. 7 - 13.
This study focused on the effects of phenobarbital, a hepatic-enzyme inducer, on verapamil. Seven healthy
male volunteers with an average weight of 78.8 kg participated in the study. The patients received either an single oral
verapamil dose of 80 mg or a single intravenous verapamil dose of 0.15 mg/kg over 3 minutes. A summary of the some
of data obtained from this experiment is given below.
1.
3.
Dose (mg/kg)
AUC
AUMC
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
MRT
iv
k
e
t
1 2
Oral Dosing
4.
5.
6. The plasma concentration ( ) of verapamil at 1 hour after the iv dose was given.
8. , the absolute bioavailability of oral verapamil.
Cp
0
V
d
Cp
AUC
0 1
f
Oral Dosing
Zidovudine (Problem 8 - 9)
Trang, J., et al., "Zidovudine bioavailability and linear pharmacokinetics in female B6C3F1 mice", Drug Metabolism and Disposi-
tion Vol, 21 (1993), p.189 - 193.
Zidovudine (AZT) is a potent inhibitor of HIV-1 during viral replication. It has been approved for the treat-
ment of AIDS. In this study a 30 mg/kg dose of AZT was given to mice either iv or orally. :A summary of the some
of data obtained from this experiment is given below.
1.
3.
4.
Dose (mg/kg)
AUC
AUMC
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
MRT
iv
k
e
t
1 2
Cp
0
Oral Dosing
5.
6. The plasma concentration ( ) of zidovudine at 1 hour after the iv dose was given.
8. , the absolute bioavailability of oral zidovudine.
9 .
10.
V
d
Cp
AUC
0 1
f
MRT
oral
MAT
oral
k
a
t
peak
Cp
max
CHAPTER 8 Bioavailability, Bioequivalence,
and Drug Selection
Author: Rasma Chereson
Reviewer: Umesh Banakar
OBJECTIVES
1. Given sufficient data to compare an oral product with another oral product or an
IV product, the student will estimate (III) the bioavailability (compare AUCs) and
judge (VI) professional acceptance of the product with regard to bioequivalence
(evaluate (VI) AUC, and ).
3. The student will be able to calculate (III) the absolute bioavailability of drug prod-
ucts.
4. The student will be able to discuss (II) the various factors affecting bioavailability.
5. The student will be able to discuss (II) the various methods of assessing bioavail-
ablity.
6. The student will be able to discuss (II) In Vivo / In Vitro Correlations.
7. The student will be able to enumerate (II) FDA requirements regarding bioequiva-
lence.
8. The student shall be able to utilize (III) the FDA Orange Book to make drug
product selections.
9. The student shall be able to discuss (II) and utilize (III) reasonalble guidelines
regarding drug product selections.
T
p
C
p
( )
max
Bioavailability, Bioequivalence, and Drug Selection
8.1 Bioavailability, Bioequivalence and Drug Product Selection
Bioavailability and bioequivalence of drug products, and drug product selection
have emerged as critical issues in pharmacy and medicine during the last three
decades. Concern about lowering health care costs has resulted in a tremendous
increase in the use of generic drug products; currently about one half of all pre-
scriptions written are for drugs that can be substituted with a generic product (1).
Over 80% of the approximately 10,000 prescription drugs available in 1990 were
available from more than one source (2). With the increasing availability and use
of generic drug products, health care professionals are confronted with an
ever-larger array of multisource products from which they must select those that
are therapeutically equivalent.
This phenomenal growth of the generic pharmaceutical industry and the abun-
dance of multisource products have prompted some questions among many health
professionals and scientists regarding the therapeutic equivalency of these prod-
ucts, particularly those in certain critical therapeutic categories such as anticonvul-
sants and cardiovasculars (1, 3-5). Inherent in the currently accepted guidelines
for product substitution is the assumption that a generic drug considered to be
bioequivalent to a brand-name drug will elicit the same clinical effect. As straight-
forward as this statement regarding bioequivalence appears to be, it has generated
a great deal of controversy among scientists and professionals in the health care
field. Numerous papers in the literature indicate that there is concern that the cur-
rent standards for approval of generic drugs may not always ensure therapeutic
equivalence (6-18).
The availability of different formulations of the same drug substance given at the
same strength and in the same dosage form poses a special challenge to health care
professionals, making these issues very relevant to pharmacists in all practice set-
tings. Since pharmacists play an important role in product-selection decisions,
they must have an understanding of the principles and concepts of bioavailability
and bioequivalence.
8.1.1 RELATIVE AND ABSOLUTE BIOAVAILABILITY
Bioavailability is a pharmacokinetic term that describes the rate and extent to
which the active drug ingredient is absorbed from a drug product and becomes
available at the site of drug action. Since pharmacologic response is generally
related to the concentration of drug at the receptor site, the availability of a drug
from a dosage form is a critical element of a drug product's clinical efficacy. How-
ever, drug concentrations usually cannot be readily measured directly at the site of
action. Therefore, most bioavailability studies involve the determination of drug
concentration in the blood or urine. This is based on the premise that the drug at
the site of action is in equilibrium with drug in the blood. It is therefore possible to
obtain an indirect measure of drug response by monitoring drug levels in the blood
or urine. Thus, bioavailability is concerned with how quickly and how much of a
drug appears in the blood after a specific dose is administered. The bioavailability
of a drug product often determines the therapeutic efficacy of that product since it
affects the onset, intensity and duration of therapeutic response of the drug. In
most cases one is concerned with the extent of absorption of drug, (that is, the frac-
tion of the dose that actually reaches the bloodstream) since this represents the
"effective dose" of a drug. This is generally less than the amount of drug actually
administered in the dosage form. In come cases, notably those where acute condi-
tions are being treated, one is also concerned with the rate of absorption of a drug,
since rapid onset of pharmacologic action is desired. Conversely, these are
instances where a slower rate of absorption is desired, either to avoid adverse
effects or to produce a prolonged duration of action.
"Absolute" bioavailability, F, is the fraction of an administered dose which actually
reaches the systemic circulation, and ranges from F = 0 (no drug absorption) to F =
1 (complete drug absorption). Since the total amount of drug reaching the sys-
temic circulation is directly proportional to the area under the plasma drug concen-
tration as a function of time curve (AUC), F is determined by comparing the
respective AUCs of the test product and the same dose of drug administered intra-
venously. The intravenous route is the reference standard since the dose is, by def-
inition, completely available.
(EQ 8-1)
(where AUC
EV
and AUC
IV
are, respectively, the area under the plasma concentra-
tion-time curve following the extravascular and intravenous administration of a
given dose of drug. Knowledge of F is needed to determine an appropriate oral
dose of a drug relative to an IV dose.
"Relative" or Comparative bioavailability refers to the availability of a drug
product as compared to another dosage form or product of the same drug given in
the same dose. These measurements determine the effects of formulation differ-
ences on drug absorption. The relative bioavailability of product A compared to
product B, both products containing the same dose of the same drug, is obtained by
comparing their respective AUCs.
(EQ 8-2)
F
AUC
ev
AUC
iv
----------------- =
RelativeBioavailabilty
AUC
A
AUC
B
--------------- =
where drug product B is the reference standard. When the bioavailability of a
generic product is considered, it is usually the relative bioavailability that is
referred to. A more general form of the equation results from considering the pos-
sibility of different doses,
(EQ 8-3)
The difference between absolute and relative bioavailability is illustrated by the
following hypothetical example. Assume that an intravenous injection (Product
A) and two oral dosage forms (Product B and Product C), all containing the same
dose of the same drug, are given to a group of subjects in a crossover study. Fur-
thermore, suppose each product gave the values for AUC indicated in Table 8-1 on
page 4.
TABLE 8-1. Data for Absolute and Relative Bioavailability
The F for Product B and Product C is 50% (F = 0.5) and 40% (F = 0.4), respec-
tively. However, when the two oral products are compared, the relative bioavail-
ability of Product C as compared to Product B is 80%.
8.1.2 FACTORS INFLUENCING BIOAVAILABILITY
Before the therapeutic effect of an orally administered drug can be realized, the
drug must be absorbed. The systemic absorption of an orally administered drug in
a solid dosage form is comprised of three distinct steps:
1. disintegration of the drug product
2. dissolution of the drug in the fluids at the absorption site
3. transfer of drug molecule across the membrane lining the gastrointestinal tract into the systemic
circulation.
Drug Product Area Under the Curve (mcg/ml) x hr
A Intravenous injection 100
B Oral dosage form, brand or reference standard 50
C Oral dosage form, generic Product 40
ComparativeBioavailability
AUC
Generic
Dose
Generic
-----------------------------
AUC
Brand
Dose
Brand
-------------------------
----------------------------- =
Any factor that affects any of these three steps can alter the drug's bioavailability
and thereby its therapeutic effect. While there are more than three dozen of these
factors that have been identified (19-38), the more significant ones are summarized
here.
The various factors that can influence the bioavailability of a drug can be broadly
classified as dosage form-related or patient-related. Some of these factors are
listed in Table 8-2 on page 5 and Table 8-3 on page 5, respectively.
TABLE 8-2 Bioavailability Factors related to the dosage form
TABLE 8-3 Bioavailability Factors Related to the patient
The physical and chemical characteristics of a drug as well as its formulation are
of prime importance in bioavailability because they can affect not only the absorp-
tion characteristics of the drug but also its stability. Since a drug must be dissolved
to be absorbed, its rate of dissolution from a given product must influence its rate
of absorption. This is particularly the case for sparingly soluble drugs. All the fac-
tors listed in Table 8-2 on page 5 can alter the dissolution rate of the drug, its bio-
availability, and ultimately, its therapeutic performance.
One of the more important factors that affects the dissolution rate of slowly dis-
solving substances is the surface area of the dissolving solid (39). Peak blood lev-
els occurred much faster with the smaller particles than the larger ones, primarily
Physicochemical properties of the drug Formulation and manufacturing variables
Particle size
Crystalline structure
Degree of hydration of crystal
Salt or ester form
Amount of disintegrant
Amount of lubricant
Special coatings
Nature of diluent
Compression force
Physiologic factors Interactions with other substances
Variations in absorption power along GI tract
Variations in pH of GI fluids
Gastric emptying rate
Intestinal motility
Perfusion of GI tract
Presystemic and first-pass metabolism
Age, sex, weight
Disease states
Food
Fluid volume
Other drugs
as a result of their faster dissolution rate. Particle size can also have a significant
effect on AUC(40). Serum levels of phenytoin after administration of equal doses
containing micronized (formulation G) and conventional (formulation F) drug
were measured. Based on the AUC, almost twice as much phenytoin was
absorbed after the micronized preparation (40).
There are numerous reports of the effects of formulation and processing variables
on the dissolution of active ingredients from drug products; an apparently inert
ingredient may affect drug absorption. For example, magnesium stearate, a lubri-
cant, commonly used in tablet and capsule formulations, is water-insoluble and
water-repellent. Its hydrophobic nature tends to retard drug dissolution by pre-
venting contact between the solid drug and the aqueous GI fluids. Thus, increas-
ing the amount of magnesium stearate in the formulation results in a slower
dissolution rate of the drug, and decreased bioavailability(34) .
The nature of the dosage form itself may have an effect on drug absorption charac-
teristics. The major pharmaceutical dosage forms for oral use are listed in Table 8-
4 on page 6 in order of decreasing bioavailability of their active ingredients. The
decreasing bioavailability is related to the number of steps involved in the absorp-
tion process following administration. The greater the number of steps a product
must undergo before the final absorption step, the slower is the availability and the
greater is the potential for bioavailability differences to occur. Thus, solutions
(elixirs, syrups, or simple solutions) generally result in faster and more complete
absorption of drug, since a dissolution step is not required. Enteric-coated tablets,
on the other hand, do not even begin to release the drug until the tablets empty
from the stomach, resulting in poor and erratic bioavailability.
TABLE 8-4 Bioavailability and oral Dosage Forms
Bioavailability studies with pentobarbital from various dosage forms show the
absorption rate of pentobarbital after administration in various oral dosage forms
decreased in the following order: aqueous solution > aqueous suspension of the
free acid > capsule of the sodium salt > tablet of the free acid (41).
In addition to the dosage form-related factors identified above, bioavailability may
also be affected by a variety of physiologic and clinical factors related to the
patient (Table 8-3 on page 5). Considerable inter-subject differences in the bio-
Fastest availability
Slowest availability
Solutions
Suspensions
Capsules
Tablets
Coated tablets
Controlled-release formulations
availability of some drugs have been observed. These can often be attributed to
individual variations in such factors as GI motility, disease state and concomi-
tantly-administered food or drugs.
One example of the myriad of physiologic factors that can affect the bioavailability
of an orally-administered drug is a patient's gastric emptying rate. Since the prox-
imal small intestine is the optimum site for drug absorption, a change in the stom-
ach emptying rate is likely to alter the rate, and possibly the extent, of drug
absorption. Any factor that slows the gastric emptying rate may thus prolong the
onset time for drug action and reduce the therapeutic efficacy of drugs that are pri-
marily absorbed from the small intestine. In addition, a delay in gastric emptying
could result in extensive decomposition and reduced bioavailability of drugs that
are unstable in the acidic media of the stomach (e.g. penicillins and erythromycin).
Differences in stomach emptying among individuals have been implicated as a
major cause of variations in the bioavailability of some drugs, particularly those
with acid-resistant enteric coatings. In a study (42), after the administration of 1.5
g acetaminophen to 14 patients, the maximum plasma concentration ranged from
7.4 to 37 mcg/ml, and the time to reach the maximum concentration ranged from
30 to 180 minutes. Both these parameters of bioavailability were linearly related
to the gastric emptying half-life found in each patient.
There are numerous factors that affect gastric emptying rate (Table 8-5 on page 8)
(43). Factors such as a patient's emotional state, certain drugs, type of food
ingested and even a patient's posture can alter the time course and extent of drug
absorption.
TABLE 8-5 Factors influencing Gastric Emptying Rate
Since drugs are generally administered to patients who are ill, it is important to
consider the effects of the disease process on the bioavailability of the drug. Dis-
ease states, particularly those involving the GI tract, such as celiac disease, Crohn's
disease, achlorhydria, and hypermotility syndromes can certainly alter the absorp-
tion of a drug (32). In addition, some diseases concerning the cardiovascular sys-
tem and the liver may also alter circulating drug levels after oral dosing.
Drugs are frequently taken with food, and patients often use mealtimes to remind
them to take their medications. However, food can have a significant effect on the
bioavailability of drugs. The influence of food on drug absorption has been recog-
FACTOR
INFLUENCE ON GASTRIC
EMPTYING RATE
Increased viscosity of stomach contents decreased
Body position
lying on left side decreased
Emotional state
stress
depression
anxiety
increased or decreased
decreased
increased
Activity, exercise decreased
Type of meal
fatty acids, fats
carbohydrates
amino acids
decreased
decreased
decreased
pH of stomach contents
decreased
increased
decreased
increased
Disease states
gastric ulcers
Crohn's disease
hypothyroidism
hyperthyroidism
decreased
decreased
decreased
increased
Drugs
atropine
propantheline
narcotic analgesics
amitriptyline
metoclopramide
decreased
decreased
decreased
decreased
increased
nized for some time, and several reviews have been published on the influence of
food on drug bioavailability (30-32, 36, 44). Food may influence drug absorption
indirectly, through physiological changes in the GI tract produced by the food,
and/or directly, through physical or chemical interactions between the drug mole-
cules and food components. When food is ingested, stomach emptying is delayed,
gastric secretions are increased, stomach pH is altered, and splanchnic blood flow
may increase. These may all affect bioavailability of drugs. Food may also inter-
act directly with drugs, either chemically (e.g. chelation) or physically, by adsorb-
ing the drug or acting as a barrier to absorption. In general, gastrointestinal
absorption of drugs is favored by an empty stomach, but the nature of drug-food
interactions is complex and unpredictable; drug absorption may be reduced,
delayed, enhanced or unaffected by the presence of food. Table 8-6 on page 9
summarizes some of the studies that have indicated the effect of food on the bio-
availability of a variety of drugs.
TABLE 8-6 Effect of Food on Drug Absorption
The effect of food and type of diet on the bioavailability of erythromycin is shown
in a study by Welling (45). The absorption of the antibiotic is significantly
reduced when it is administered with food compared with its absorption under fast-
ing conditions. This reduced absorption is primarily a result of degradation of the
acid-labile erythromycin due to prolonged retention in the stomach.
Delayed absorption due to food has been demonstrated in the case of cephradine in
a study by Mischler (46). Similar results have been observed with other oral ceph-
alosporins.
Some drugs demonstrate enhanced bioavailability in the presence of food. This
has been attributed to a variety of factors, including improved compound solubility
and more time for dissolution because of delayed gastric emptying. In the case of
Reduced Absorption Delayed Absorption Increased Absorption
Ampicillin
Aspirin
Atenolol
Captopril
Erythromycin
Ethanol
Hydrochlorothiazide
Penicillins
Tetracyclines (most)
Acetaminophen
Aspirin
Cephalosporins (most)
Diclofenac
Digoxin
Furosemide
Nitrofurantoin
Sulfadiazine
Sulfisoxazole
Chlorothiazide
Diazepam
Griseofulvin
Hydralazine
Labetalol
Metoprolol
Nitrofurantoin
Propranolol
Riboflavin
Source: Ref. 32
highly metabolized agents, such as propranolol and metoprolol, the enhanced
availability may be due to increased splanchnic blood flow causing reduced
first-pass clearance. The circulating levels of these drugs dosed under fasting and
non-fasting conditions have been presented in a study by Melander (47).
The volume of fluid with which an orally administered dose is taken can also affect
a drug's bioavailability. Drug administration with a larger fluid volume will gener-
ally improve its dissolution characteristics and may also result in more rapid stom-
ach emptying. Thus, more efficient and more reliable drug absorption can be
expected when an oral dosage form is administered with a larger volume of fluid.
(45) .
Interactions between drugs can have a significant effect on the bioavailability of
one or both drugs. Such interactions may be direct, as in chelation of tetracycline
by polyvalent metal ions in antacids or the adsorption of digoxin by
cholestyramine resin, or indirect, as with the increased rate of acetaminophen
absorption due to the increased gastric emptying rate produced by metoclopra-
mide. Most of the reported drug-drug interactions have resulted in a reduction in
the rate and/or extent of drug absorption, the most frequent causes being complex-
ing of a drug with other substances, reduced GI motility and alterations in drug
ionization (24, 30, 32, 48, 49). Table 8-7 on page 10 summarizes the major mech-
anisms of GI drug interactions affecting bioavailability.
TABLE 8-7 Drug interactions affecting absorption
An example of a direct interaction between drugs affecting bioavailability is the
interaction between iron and tetracycline. This is a well-documented and clini-
cally significant interaction which can result in a dramatic reduction in serum con-
centration of tetracycline (50).
The above potential sources of alteration in a drug's bioavailability must be kept in
mind when attempting to evaluate the relative performance of drug products on the
1. Change in gastric or intestinal pH
2. Change in gastrointestinal motility
3. Change in gastrointestinal perfusion
4. Interference with mucosal function (drug-induced malabsorption syndromes)
5. Chelation
6. Exchange resin binding
7. Aadsorption
8. Solution in poorly absorbable liquid
Source: Ref. 23
basis of studies performed with healthy human volunteers. These studies are gen-
erally performed under tightly-controlled fasting conditions in the absence of other
drugs. In practice, however, drugs are seldom taken under such ideal conditions,
and the factors leading to changes in drug absorption must be taken into consider-
ation.
8.1.3 METHODS OF ASSESSING BIOAVAILABILITY
Bioavailability testing is a means of predicting the clinical efficacy of a drug; the
estimation of the bioavailability of a drug in a given dosage form is direct evidence
of the efficiency with which a dosage form performs its intended therapeutic func-
tion.
The bioavailability of a drug substance formulated into a pharmaceutical product
is fundamental to the goals of dosage form design and essential for the clinical effi-
cacy of the medication. Thus, bioavailability testing, which measures the rate and
extent of drug absorption, is a way to obtain evidence of the therapeutic utility of a
drug product. Bioavailability determinations are performed by drug manufacturers
to ensure that a given drug product will get the therapeutic agent to its site of
action in an adequate concentration. Bioavailability studies are also carried out to
compare the availability of a drug substance from different dosage forms or from
the same dosage form produced by different manufacturers.
In-vivo methods One method for assessing the bioavailability of a drug product is through the dem-
onstration of a clinically significant effect. However, such clinical studies are
complex, expensive, time-consuming and require a sensitive and quantitative mea-
sure of the desired response. Further, response is often quite variable, requiring a
large test population. Practical considerations, therefore, preclude the use of this
method except in initial stages of development while proving the efficacy of a new
chemical entity.
Quantification of pharmacologic effect is another possible way to assess a drug's
bioavailability. This method is based on the assumption that a given intensity of
response is associated with a particular drug concentration at the site of action;
e.g., variation of miotic response intensity can be directly related to the oral dose
of chlorpromazine. However, monitoring of pharmacologic data is often difficult,
precision and reproducibility are difficult to establish, and there are only a limited
number of pharmacologic effects (e.g. heart rate, body temperature, blood sugar
levels) that are applicable to this method.
Because of these limitations, alternative methods have been developed to predict
the therapeutic potential of a drug. The current method to assess the clinical per-
formance of a drug involves measurement of the drug concentrations in the blood
or urine. In such studies a single dose of the drug product is administered to a
panel of normal, healthy adult (18- to 35-year old) subjects. Blood and/or urine
samples are collected over a period of time following administration and are ana-
lyzed for drug content. Based on the blood concentration as a function of time
and/or urinary excretion profile, inferences are drawn regarding the rate and extent
of absorption of the drug. These studies are relatively easy to conduct and require
a limited number of subjects.
Blood level studies- Blood level studies are the most common type of human bioavailability studies,
and are based on the assumption that there is a direct relationship between the con-
centration of drug in blood or plasma and the concentration of drug at the site of
action. By monitoring the concentration in the blood, it is thus possible to obtain
an indirect measure of drug response. Following the administration of a single
dose of a medication, blood samples are drawn at specific time intervals and ana-
lyzed for drug content. A profile is constructed showing the concentration of drug
in blood at the specific times the samples were taken . The key parameters to note
are:
1. AUC , The area under the plasma concentration-time curve, The AUC is proportional to the
total amount of drug reaching the systemic circulation, and thus characterizes the extent of
absorption.
2. C
max
, The maximum drug concentration. The maximum concentration of drug in the plasma
is a function of both the rate and extent of absorption. C
max
will increase with an increase in
the dose, as well as with an increase in the absorption rate.
3. T
max
, The time at which the Cmax occurs. The T
max
reflects the rate of drug absorption, and
decreases as the absorption rate increases.
Bioavailability (the rate and extent of drug absorption) is generally assessed by the
determination of these three parameters.
Since the AUC is representative of, and proportional to, the total amount of drug
absorbed into the circulation, it is used to quantitate the extent of drug absorption.
The calculation of AUC has been discussed in Chapter 4. A variety of pharmacok-
inetic methods have been suggested for the calculation of absorption rates (51-56).
For clinical purposes, it is generally sufficient to determine C
max
and T
max
. If all
other factors are constant, such as the extent of absorption and rate of elimination,
then C
max
is proportional to the rate of absorption and T
max
is inversely propor-
tional to the absorption rate. Thus, the faster the absorption of a drug the higher
the maximum concentration will be and the less time it will take to reach the max-
imum concentration.
Urinary Excretion Data - An alternative bioavailability study measures the cumulative amount of unchanged
drug excreted in the urine. These studies involve collection of urine samples and
the determination of the total quantity of drug excreted in the urine as a function of
0
time. These studies are based on the premise that urinary excretion of the
unchanged drug is directly proportional to the plasma concentration of total drug.
Thus, the total quantity of drug excreted in the urine is a reflection of the quantity
of drug absorbed from the gastrointestinal tract. Consider the following example:
two products, A and B, each containing 100 mg of the same drug are administered
orally. A total of 80 mg of drug is recovered in the urine from Product A, but only
40 mg is recovered from Product B. This indicates that twice as much drug was
absorbed from Product A as from Product B. (The fact that neither product
resulted in excretion of the entire dose might be due to the existence of other routes
of elimination, e.g. metabolism).
This technique of studying bioavailability is most useful for those drugs that are
not extensively metabolized prior to urinary elimination. As a rule-of-thumb,
determination of bioavailability using urinary excretion data should be conducted
only if at least 20% of a dose is excreted unchanged in the urine after an IV dose
(56). Other conditions which must be met for this method to give valid results
include:
1. the fraction of drug entering the bloodstream and being excreted intact by the kidneys must
remain constant.
2. collection of the urine has to continue until all the drug has been completely excreted (five times
the half-life
1
).
Urinary excretion data are primarily useful for assessing extent of drug absorption,
although the time course for the cumulative amount of drug excreted in the urine
can also be used to estimate the rate of absorption. In practice, these estimates are
subject to a high degree of variability, and are less reliable than those obtained
from plasma concentration-time profiles (57). Thus, urinary excretion of drug is
not recommended as a substitute for blood concentration data; rather, these studies
should be used in conjunction with blood level data for confirmatory purposes.
Single-dose versus
Multiple-Dose-
Most bioavailability evaluations are made on the basis of single-dose administra-
tion. The argument has been made that single doses are not representative of the
actual clinical situation, since in most instances, patients require repeated adminis-
tration of a drug. When a drug is administered repeatedly at fixed intervals, with
the dosing frequency less than five half-lives, drug will accumulate in the body and
eventually reach a plateau, or a steady-state
At steady-state, the amount of drug eliminated from the body during one dosing
interval is equal to the available dose (rate in = rate out); therefore, the area under
the curve during a dosing interval at steady-state is equal to the total area under the
curve obtained when a single dose is administered. This AUC can therefore be
1. Half life is defined as the length of time required to lose 50% of the drug in the body, assuming first order elimination.
used to assess the extent of absorption of the drug, as well as its absolute and rela-
tive bioavailability.
Multiple-dose administration has several advantages over single-dose bioavailabil-
ity studies, as well as some limitations. These are summarized in Table 8-8 on
page 14 (54, 59).
TABLE 8-8 Multiple dose vs. single dose studies in bioavailability studies
When a drug obeys linear, first-order kinetics, it is possible to estimate the results
that would be obtained during multiple dosing from single-dose studies. Projec-
tion is easily made with regard to the extent of absorption, using the AUC follow-
ing a single dose. Results from bioequivalence studies indicate that conclusions on
the extent of absorption as assessed by the AUC can be made equally well on the
basis of a single or multiple dose study (60). Assessing the rate of absorption dur-
ing multiple-dosing from single-dose studies has presented a greater problem.
Although a number of single-dose characteristics have been suggested as indica-
tors of rate of absorption during multiple dosing (e.g. percent peak-trough fluctua-
tion and percent peak-trough swing), results of bioequivalence studies indicate that
only the plateau time (the time during which the concentration exceeds 75% of the
maximum concentration, t 75% Cmax) and the residual concentration at the end of
the dose interval produce consistent results in assessing the rate of absorption in
single- and multiple-dose studies (54, 61).
In the case of drugs exhibiting nonlinear kinetics, establishing a linear relationship
between single- and multiple-dose bioavailability data has proven to be a difficult
task. Thus, it has been recommended that for drugs with either saturable elimina-
tion or a nonlinear first-pass effect, steady-state studies be carried out to assess
their bioavailability (62).
Advantages:
Eliminates the need to extrapolate the plasma concentration profiles to obtain the total AUC
after a single dose
Eliminates the need for a long wash-out period between doses
More closely reflects the actual clinical use of the drug
Allows blood levels to be measured at the same concentrations encountered therapeutically
Because blood levels tend to be higher than in the single-dose method, quantitative determina-
tion is easier and more reliable
Saturable pharmacokinetics, if present, can be more readily detected at steady-state
Limitations:
Requires more time to complete
More difficult and costly to conduct (requiring prolonged monitoring of subjects
Greater problems with compliance control
Greater exposure of subjects to the test drug, increasing the potential for adverse reactions
8.1.4 STUDY DESIGN
Bioavailability studies involve the administration of the test dosage form to a panel
of subjects, after which blood and/or urine samples are collected and analyzed for
drug content. Based on the concentration profile of the drug, a judgement is made
regarding the rate and extent of absorption of the drug. Normally, the study is con-
ducted in a group of healthy, male subjects who are of normal height and weight,
and range in age from 18 to 35 years (6). Questions have been raised regarding the
extent to which such a population reflects the performance of a given drug product
in a actual patient population. At first glance, it would seem that bioavailability
should be determined in patients actually suffering from the disease for which the
drug is intended, or in patients representative of the age and sex of subjects who
would be using the drug. However, there are several very good reasons for using
healthy volunteers rather than patients. In bioavailability studies, it is assumed
that there are no physiologic changes in the subjects during the course of the study.
If actual patients were used, this would not be a valid assumption, due to possible
changes in the disease state. Another potential problem with using patients is that
many patients take more than one drug. This could result in a drug-drug interac-
tion which could influence the bioavailability of the test drug. In addition, diet and
fluid volume intake, both of which can influence a drug's bioavailability are more
difficult to control in a patient population than in a panel of healthy test subjects.
In general, it is more difficult with patients to have a standardized set of conditions
which are necessary for a dependable bioavailability study. However, it must be
recognized that factors that may affect a drug's performance in a patient population
may not be detected in a group of healthy subjects. Thus, it is best to conduct a
separate study in patients to determine if the disease, for which the drug is intended
to be used, alters the bioavailability of the drug.
Other important considerations in the methodology of a bioavailability study are
sample size, period of trial, and sampling. For statistical purposes, twelve subjects
are considered to be a minimum sample size. Otherwise there will not be enough
data to draw valid conclusions (63). The bioavailability testing period should be of
a sufficient length of time to ensure that drug absorption has been completed. This
length of time is at least three times the half-life of the drug; generally a period of
four to five times the half-life is used (63, 64). Blood samples should be taken
with sufficient frequency to permit an accurate determination of tmax, Cmax and
AUC.
8.1.5 IN-VITRO DISSOLUTION AND BIOAVAILABILITY
Pharmaceutical scientists have for many years been attempting to establish a corre-
lation between some physicochemical property of a dosage form and the biological
availability of the drug from that dosage form. The term commonly used to
describe this relationship is "in-vitro/in-vivo correlation" (65). Specifically, it is
felt that if such a correlation could be established, it would be possible to use
in-vitro data to predict a drug's in-vivo bioavailability. This would drastically
reduce, or in some cases, completely eliminate the need for bioavailability tests.
The desirability for this becomes clear when one considers the cost and time
involved in bioavailability studies as well as the safety issues involved in adminis-
tering drugs to healthy subjects or patients. It would certainly be preferable to be
able to substitute a quick, inexpensive in-vitro test for in-vivo bioavailability stud-
ies. This would be possible if in-vitro tests could reliably and accurately predict
drug absorption and reflect the in-vivo performance of a drug in humans.
Disintegration Tests- The early attempts to establish an indicator of drug bioavailability focused on dis-
integration as the most pertinent in-vitro parameter. The first official disintegra-
tion test appeared in the United States Pharmacopeia (USP) in 1950. However,
while it is true that a solid dosage form must disintegrate before significant disso-
lution and absorption can occur, meeting the disintegration test requirement only
insures that the dosage form (tablet) will break up into sufficiently small particles
in a specified length of time. It does not ensure that the rate of solution of the drug
is adequate to produce suitable blood levels of the active ingredient. Therefore,
while the test for tablet disintegration is very useful for quality control purposes in
manufacturing, it is a poor index of bioavailability.
Dissolution Tests- Since a drug must go into solution before it can be absorbed, and since the rate at
which a drug dissolves from a dosage form often determines its rate and/or extent
of absorption, attention has been directed at the dissolution rate. It is currently
considered to be the most sensitive in-vitro parameter most likely to correlate with
bioavailability.
Official dissolution tests - There are two official USP dissolution methods: Apparatus 1, (basket method),
and Apparatus 2 (paddle method). For details of these dissolution tests, the reader
is recommended to consult USPXXII/NFXVII (66).
Dissolution tests are an extremely valuable tool in ensuring the quality of a drug
product. Generally, product-to-product variations are due to formulation factors,
such as particle size differences, excessive amounts of lubricant and coatings.
These factors are reactive to dissolution testing. Thus, dissolution tests are very
effective in discriminating between and within batches of drug product(s). The
dissolution test, in addition, can exclude definitively any unacceptable product.
Limitations of
dissolution tests-
There are, however, problems with in-vitro dissolution testing which should be
noted - problems which make correlation with in- vivo availability difficult. The
first is related to instrument variance and the absence of a standard method. The
tests described in the USP are but a few of the large number of dissolution methods
proposed to predict bioavailability. Since the dissolution rate of a dosage form is
dependent on the methodology used in the dissolution test, changes in the appara-
tus, dissolution medium, etc., can dramatically modify the results. Table 8-9 on
page 17 lists some of the factors related to the dissolution testing device that can
affect the dissolution rate of the drug.
TABLE 8-9 Device factors affecting dissolution
Another significant problem is related to the difference between the in-vitro and
in-vivo environments in which dissolution occurs. In-vitro studies are generally
carried out under controlled conditions in one, or perhaps two, standardized sol-
vents. The in-vivo environment (the gastrointestinal tract), on the other hand, is a
continuously changing, complex environment. There are many variables which
can affect the dissolution rate of a drug in the gastrointestinal tract, including pH,
enzyme secretions, surface tension, motility, presence of other substances and
absorption surfaces (68). Thus, drugs frequently dissolve in the body at rates quite
different from those observed in an in-vitro test situation. Most of the official dis-
solution tests tend to be acceleration dissolution tests which bear limited or no
relationship with in-vivo dissolution.
Adding to the complexity of correlating dissolution with in-vivo absorption are
factors such as drug-drug interactions, age, food effects, health, genetic back-
ground, biorhythm and physical activity (32, 69). All these factors may have an
effect on the rate and extent of absorption of a drug. Thus, the in-vivo environ-
ment is far more complex, variable, and unpredictable than any in-vitro test envi-
ronment, making in-vitro / in-vivo correlations very difficult. A simple dissolution
test in a standardized vehicle cannot reflect the in vivo absorption of a drug across a
population (70).
Parameters used- Proper selection of the in-vitro and in-vivo parameters to be correlated is critical
in achieving a meaningful correlation. The in-vitro parameter should be selected
that has the greatest effect on the absorption characteristics of the drug (71). There
are several approaches to establishing a correlation between the dissolution of a
1. Degree of agitation
2. Size and shape of container
3. Composition of dissolution medium
pH
ionic strength
viscosity
surface tension
4. Temperature of dissolution medium
5. Volume of dissolution medium
6. Evaporation
7. Hydrodynamics (flow pattern)
Source: Ref. 67
drug in in- vitro and the bioavailability of a drug in-vivo. The in-vitro - in-vivo
correlative methods used most often are of the single-point type where the dissolu-
tion rate (expressed as the percent of drug dissolved in a given time, or the time
required for a given percent of the drug to dissolve) is correlated to a certain
parameter of the bioavailability. Examples of in-vivo parameters used include
Cmax, AUC, time to reach half-maximal plasma concentration, the average
plasma concentration after 0.5 or 1 hour, maximum urinary excretion rate, and
cumulative percent excreted in urine after a given time (71- 78). According to
Wagner, the best in-vitro variable to use is the time for 50 percent of the drug to
dissolve, and the best variable from in-vivo data to use is the time for 50 percent of
the drug to be absorbed (79).
Ideally, one would hope to find a linear relationship between some measurement of
the dissolution test and some measurement based on bioavailability studies.
Unfortunately, most attempts to accomplish this objective have failed.
8.1.6 IN-VITRO / IN-VIVO CORRELATION STUDIES-
There have been many attempts to establish in-vitro / in-vivo correlations for a
large variety of drugs. Some of these studies have been summarized by Welling,
Banakar, and Abdou (71, 80-82).
While there are many published examples of satisfactory correlations between
absorption parameters and in-vitro dissolution tests, most studies have resulted in
poor, or moderate, in-vitro - in-vivo correlations, often involving agreement with
only one of the critical bioavailability parameters. Moreover, the positive correla-
tions that have been found generally apply only to the specific formulation studied.
There have been instances where the dissolution rates or various formulations of
the same drug have been significantly different, yet little or no difference was
observed in their bioavailability parameters (83-85). There have also been cases
where a drug has failed to meet compendia dissolution standards but has demon-
strated adequate bioavailability (86). Welling states: "To the writer's knowledge,
there have been no studies that have accurately correlated in- vitro and in-vivo data
to the point that the use of upper and lower limits for in-vitro dissolution parame-
ters can be confidently used to predict in-vivo behavior and, therefore, to replace
in-vivo testing" (71).
Even if an in-vitro test could be designed that would accurately reflect the dissolu-
tion process in the gastrointestinal tract, dissolution is only one of many factors
that affect a drug's bioavailability. For example, saturable presystemic metabolism
may affect the extent of drug absorption, but this would not be predicted by an
in-vitro test. Dissolution studies also would not predict poor bioavailability due to
instability in gastric fluid or complexation with another drug or food component.
Thus, the ultimate evaluation a drug product's performance under the conditions
expected in clinical therapy must be an in-vivo test; a dissolution test is unlikely to
entirely replace bioavailability testing (70, 87, 88). In-vitro methods are important
in the development and optimization of dosage forms while in-vivo tests are essen-
tial in obtaining information on the behavior of medication in living organisms.
One cannot be substituted for the other (69).
8.2 Bioequivalence
Definitions With the phenomenal increase in the availability of generic drugs in recent years,
the issues of bioavailability and bioequivalence have received increasing attention.
In order for a drug product to be interchangeable with the pioneer (innovator or
brand name) product, it must be both pharmaceutically equivalent and bioequiva-
lent to it. According to the FDA, "pharmaceutical equivalents" are drug products
that contain identical active ingredients and are identical in strength or concentra-
tion, dosage form, and route of administration (89). However, pharmaceutical
equivalents do not necessarily contain the same inactive ingredients; various man-
ufacturers' dosage forms may differ in color, flavor, shape, and excipients. The
terms "pharmaceutical equivalents" and "chemical equivalents" are often used
interchangeably.
"Bioequivalence" is a comparison of the bioavailability of two or more drug prod-
ucts. Thus, two products or formulations containing the same active ingredient are
bioequivalent if their rates and extents of absorption are the same. When a new
formulation of an existing drug is developed, its bioavailability is generally evalu-
ated relative to the standard formulation of the originator. Indeed, a bioequiva-
lence trial against the standard formulation is the key feature of an Abbreviated
New Drug Application (ANDA) submitted to the Food and Drug Administration
by a manufacturer who wishes to produce a generic drug. For a generic drug to be
considered bioequivalent to a pioneer product, there must be no statistical differ-
ences (as specified in the accepted criteria) between their plasma concentra-
tion-time profiles. Because two products rarely exhibit absolutely identical
profiles, some degree of difference must be considered acceptable, as will be dis-
cussed later.
Since the concentration of a drug in blood is used as an assessment of its clinical
performance, inherent in the demonstration that two preparations containing
equivalent amounts of the same drug produce similar concentrations of the drug
entity in blood is the assumption that they will elicit equivalent drug responses.
Thus, two products that are deemed to be bioequivalent are also assumed to be
therapeutically equivalent, and therefore interchangeable. This principle is funda-
mental to the concept of bioequivalence and is the basic premise on which it is
founded.
In general, the FDA considers two products to be "therapeutic equivalents" if they
each meet the following criteria (90):
1. they are pharmaceutical equivalents,
2. they are bioequivalent (demonstrated either by a bioavailability measurement or an in vitro stan-
dard),
3. they are in compliance with compendial standards for strength, quality, purity and identity,
4. they are adequately labelled, and
5. they have been manufactured in compliance with Good Manufacturing Practices as established
by the FDA.
Background The first intimations of bioequivalence problems with multi-source drug products
were given by early investigations of the availability of vitamins, aspirin, tetracy-
cline, and tolbutamide (91-97). In 1974, after an extensive review of the bioavail-
ability of drugs, Koch-Weser concluded that " . . . among drugs thus far tested
bioinequivalence of different drug products has been far more common than
bioequivalence" (98). Of particular note were the studies involving digoxin; the
findings of these investigations sparked the discussion about bioequivalence
assessment that still continues today. Significant differences were seen in the bio-
availability of digoxin not only between products supplied by different companies,
but also between lots obtained from the same manufacturer (99). Because of the
narrow therapeutic range for this drug, and because the drug is utilized in the treat-
ment of cardiac patients, these findings generated a great deal of concern.
Similar reports of bioinequivalence and therapeutic inequivalence appeared for
other drugs as well, including phenytoin, phenylbutazone, chloramphenicol, tolb-
utamide and thyroid (6). The clinical significance of these reported differences in
bioavailability relates to the therapeutic index of the drug, the dose of the drug and
the nature of the disease. In 1973 the Ad Hoc Committee on Drug Product Selec-
tion of the American Pharmaceutical Association published a list of drugs with a
potential for therapeutic inequivalence based on reported evidence of bioinequiva-
lence (100). The drugs fall in three categories: "high," "moderate," or "low risk"
based on the clinical implications (Table 8-10 on page 22).
TABLE 8-10 Drugs with various risk potential for inequivalence
The concern about the bioinequivalence of some drugs led to the establishment in
1974 of the Drug Bioequivalence Study Panel of the Office of Technology Assess-
ment (OTA). The objective was to ensure that drug products of the same physical
and chemical composition would produce similar therapeutic effects. Among the
11 recommendations of the Panel was the conclusion that not all chemical equiva-
lents were interchangeable, but the goal of interchangeability was achievable for
most oral drug products (101). The Report recommended that a system should be
organized as rapidly as possible to generate an official list of interchangeable drug
products. The OTA Report, as well as the growing awareness within the scientific
and regulatory communities of bioavailability problems with marketed drug prod-
ucts, focused the attention of the FDA on bioequivalence and bioavailability prob-
lems and issues.
High Risk Potential Moderate Risk Potential Low or Negligible Risk
Potential
aminophylline
aspirin (when used in high dose
levels)
bishydroxycoumarin
digoxin
dipheylhydantoin (phenytoin)
para-aminosalicylic acid
prednisolone
prednisone
quinidine
warfarin
amphetamines
(sustained-release)
ampicillin
chloramphenicol
chlorpromazine
digitoxin
erythromycin
griseofulvin
oxytetracycline
penicillin G (buffered)
pentobarbital
phenylbutazone
phenacetin
potassium chloride (solid dosage
forms)
salicylamide
secobarbital
sulfadiazine
tetracycline
tolbutamide
acetaminophen
codeine
ferrous sulfate
hydrochlorothiazide
ephedrine
isoniazid
meprobamate
penicillin VK
sulfisoxazole
8.2.1 BIOEQUIVALENCE REGULATIONS
In 1977, the FDA implemented a series of bioavailability and bioequivalence regu-
lations which formed the basis of subsequent discussion, if not controversy, of
therapeutic equivalency of drug products (102). The regulations are divided into
two separate regulations; Subpart B - Procedures for Determining the Bioavail-
ability of Drug Products and Subpart C - Bioequivalence Requirements. While
Table 11 summarizes the key provisions of the bioavailability regulations, those
for bioequivalence requirements are summarized in Table 8-11 on page 23.
TABLE 8-11 Key provisions for bioavailabilty regulations
Criteria for establishing
a bioequivalence
requirement -
The 1977 Bioequivalence regulations set forth the following criteria and evidence
supporting the establishment of a bioequivalence requirement for a given drug
product:
1. Evidence from well-controlled clinical trials or controlled observations in patients that such
products do not give comparable therapeutic effects.
2. Evidence from well-controlled bioequivalence studies that such products are not bioequivalent
drug products.
3. Evidence that the drug products exhibit a narrow therapeutic ratio, (e.g., there is less than a
two-fold difference in the median lethal dose (LD50) and median effective dose (ED50) value
or have less than a two-fold difference in the minimum toxic concentration and minimum effec-
tive concentrations in the blood), and safe and effective use of the drug product requires careful
dosage titration and patient monitoring.
4. Competent medical determination that a lack of bioequivalence would have a serious adverse
effect in the treatment or prevention of a serious disease or condition.
5. Physicochemical evidence of any of the following:
a. The active drug ingredient has a low solubility in water--e.g., less than 5 mg/ml.
b. The dissolution rate of one or more such products is slow--e.g., less than 50 percent in
thirty minutes when tested with a general method specified by an official compendium or the
FDA.
c. The particle size and/or surface area of the active drug ingredient is critical in determining
bioavailability.
1. Defines bioavailability in terms of both the rate and extent of drug absorption.
2. Describes procedures for determining the bioavailability of drug products.
3. Sets forth requirements for submission of in vivo bioavailability data.
4. Sets forth criteria for waiver of human in vivo bioavailability studies.
5. Provides general guidelines for the conduct of in vivo bioavailability studies.
6. Imposes a requirement for filing an Investigational New Drug Application.
Source: Ref. 103
d. Polymorphs, solvates, complexes, and such, exist that could contribute to poor dissolution
and may affect absorption.
e. There is a high excipient/active drug ratio present in the drug product--e.g., greater than 5
to 1.
f. The presence of specific inactive ingredients (e.g. hydrophilic or hydrophobic excipients)
that either may be required for absorption of the active drug or may interfere with such absorp-
tion.
6. Pharmacokinetic evidence of any of the following:
a. The drug is absorbed in large part in a particular segment of the gastrointestinal tract or is
absorbed from a localized site.
b. Poor absorption of the drug, even when it is administered as a solution--e.g., less than 50
percent compared to an intravenous dose.
c. The drug undergoes first-pass metabolism in the intestinal wall or liver.
d. The drug is rapidly metabolized or excreted, requiring rapid dissolution and absorption for
effectiveness.
e. The drug is unstable in specific portions of the gastrointestinal tract, requiring special
coatings and formulations--e.g., enteric coatings, buffers, film coatings--to ensure adequate
absorption.
f. The drug follows nonlinear kinetics in or near the therapeutic range, and the rate and
extent of absorption are both important to bioequivalence.
Types of Bioequivalence
Requirements
In the event that a drug meets one or more of the above six criteria, a bioequiva-
lence requirement is established. The requirement could be either an in-vivo or an
in-vitro investigation, as specified by the FDA. The types of bioequivalence
requirements include the following:
1. An in-vivo test in humans.
2. An in-vivo test in animals that has been correlated with human in- vivo data.
3. An in-vivo test in animals that has not been correlated with human in- vivo data.
4. An in-vitro bioequivalence standard, i.e., an in-vitro test that has been correlated with human
in-vivo bioavailability data.
5. A currently available in-vitro test (usually a dissolution rate test) that has not been correlated
with human in-vivo bioavailability data.
The regulations state that in-vivo testing in humans would generally be required if
there is well-documented evidence that pharmaceutical equivalents intended to be
used interchangeably meet one of the first three criteria used to establish a
bioequivalence requirement:
1. The drug products do not give comparable therapeutic effects.
2. The drug products are not bioequivalent.
3. The drug products exhibit a narrow therapeutic ratio (as described above), and safe and effec-
tive use of the product requires careful dosage titration and patient monitoring.
Criteria for waiver of
evidence of in-vivo
bioavailability -
Although a human in-vivo test is considered to be preferable to other approaches
for the most accurate determination of bioequivalence, there is a provision in the
1977 regulations for waiver of an in-vivo bioequivalence study under certain cir-
cumstances. For some drug products, the in-vivo bioavailability of the drug may
be self-evident or unimportant to the achievement of the product's intended pur-
poses. The FDA will waive the requirement for submission of in-vivo evidence of
bioavailability or bioequivalence if the drug product meets one of the following
criteria:
1. The drug product is a solution intended solely for intravenous administration, and contains the
active drug ingredient in the same solvent and concentration as an intravenous solution that is
the subject of an approved full New Drug Application (NDA).
2. The drug product is a topically applied preparation intended for local therapeutic effect.
3. The drug product is an oral dosage form that is not intended to be absorbed, e.g., an antacid.
4. The drug product is administered by inhalation and contains the active drug ingredient in the
same dosage form as a drug product that is the subject of an approved full NDA.
5. The drug product is an oral solution, elixir, syrup, tincture or other similar soluble form, that
contains an active drug ingredient in the same concentration as a drug product that is the subject
of an approved full NDA and contains no inactive ingredient that is known to significantly
affect absorption of the active drug ingredient.
6. The drug product is a solid oral dosage form (other than enteric-coated or controlled-release)
that has been determined to be effective for at least one indication in a Drug Efficacy Study
Implementation (DESI) notice and is not included in the FDA list of drugs for which in vivo
bioequivalence testing is required.
7. The drug product is a parenteral drug product that is determined to be effective for at least one
indication in a DESI notice and shown to be identical in both active and inactive ingredients for-
mulation, with a drug product that is currently approved in an NDA. (Excluded from the waiver
provision are parenteral suspensions and sodium phenytoin powder for injection.)
According to the regulations, the bioavailability of certain drug products may be
demonstrated by evidence obtained in-vitro in lieu of in-vivo data. Thus, the FDA
also permits waiver of the in-vivo requirements if a drug product meets one of the
following criteria:
1. The drug product is one for which only an in-vitro bioequivalence requirement has been
approved by the FDA.
2. The drug product is in the same dosage form, but in a different strength, and is proportionally
similar in its active and inactive ingredients to another drug product made by the same manufac-
turer and the following conditions are met:
a. the bioavailability of this other product has been demonstrated
b. both drug products meet an appropriate in-vitro test approved by the FDA
c. the applicant submits evidence showing that both drug products are proportionally similar
in their active an inactive ingredients.
3. The drug product is shown to meet an in-vitro test that assures bioavailability, i.e., an in-vitro
test that has been correlated with in-vivo data.
4. The drug product is a reformulated product that is identical, except for color, flavor, or preserva-
tive, to another drug product made by the same manufacturer, and both of the following condi-
tions are met:
a. the bioavailability of the other product has been demonstrated.
b. both drug products meet an appropriate in vitro test approved by the FDA.
5. The drug product contains the same active ingredient and is in the same strength and dosage
form as a drug product that is the subject of an approved full NDA or Abbreviated New Drug
Application (ANDA) and both drug products meet an appropriate in-vitro test that has been
approved by the FDA.
Although the above list of criteria for waiver of an in-vivo bioavailability study is
quite lengthy, currently virtually all new tablet or capsule formulations from which
measurable amounts of drug or metabolites are absorbed into the systemic circula-
tion require a human bioequivalence study for approval (104).
TABLE 8-12 Key Provisions for bioequivalence requirements
8.2.2 STUDY DESIGN
A single-dose bioequivalency study is generally performed in normal, healthy,
adult volunteers. The subject population should be selected carefully, so that prod-
uct formulations, and not intersubject variations, will be the only significant deter-
minants of bioequivalence (105). A minimum of 12 subjects is recommended,
although 18 to 24 subjects are used to increase the data base for statistical analysis.
The test and the reference products are usually administered to the subjects in the
fasting state (overnight fast for at least 10 hours, plus 2 to 4 hours after administra-
tion of the dose), unless some other approach is more appropriate for valid scien-
tific reasons. These subjects should not take any other medication for one week
prior to the study or during the study. The bioavailability is determined by the col-
lection of either blood samples or urine samples over a period of time and mea-
surement of the concentration of drug present in the samples.
Generally, a crossover study design is used. Using this method, both the test and
the reference products are compared in each subject, so that inter-subject variables,
1. Defines procedures for establishing a bioequivalence requirement.
2. Sets forth criteria to establish a bioequivalence requirement.
3. Describes types of bioequivalence requirements.
4. Sets forth requirement for in-vitro batch testing and certification.
5. Describes requirements for marketing a drug product subject to a bioequivalence requirement.
6. Sets forth requirements for in-vivo testing of a drug product not meeting an in-vitro bioequiv-
alence standard.
Source: Ref. 103
such as age, weight, differences in metabolism, etc., are minimized. Each subject
thus acts as his own control. Also, with this design, subjects' daily variations are
distributed equally among all dosage forms or drug products being tested.
The subjects are randomly selected for each group and the sequence of drug
administration is randomly assigned. The administration of each product is fol-
lowed by a sufficiently long period of time to ensure complete elimination of the
drug (washout period) before the next administration. The washout period should
be a minimum of 10 half-lives of the administered drug (106). A waiting period of
one week between administration is usually an adequate washout period of most
drugs.
With a drug requiring a washout period of one week, a typical randomized two-
way crossover bioequivalency study is shown in Table 8-13 on page 27.
TABLE 8-13 Two way cross over design
a
10 subjects per group
Assuming that the in-vivo performances of the two formulations are to be com-
pared by examining their blood level profiles, one must be certain that an adequate
number of blood samples are taken. Blood samples should be drawn with suffi-
cient frequency to provide an accurate characterization of the drug concentra-
tion-time profile from which tmax, Cmax and AUC can be determined. Typically,
a total of 10 to 15 sampling times might be required (107). Moreover, all samples
should be taken at the same time for both the test and the reference product to per-
mit proper statistical analysis.
Additional features which contribute to good study design include:
1. All drug samples obtained for the test and reference preparations should be analyzed by the
same method.
2. Identical test conditions must be used for the two groups of subjects. For example, the types of
foods, fluid intake, physical activity, and posture should all be rigidly controlled in the study.
3. The physical characteristics of the subjects (such as age, height, weight, and health) should be
standardized.
Treatment
Group
a
Week 1 Week 2
I
II
A
B
B
A
Several important questions have been raised specifically regarding the design of
the bioequivalence tests. One of these deals with the selection of the appropriate
reference standard, since this is a critical component of a protocol (6, 108). Nor-
mally, the reference product is that available from the innovator company holding
the New Drug Application. However, in cases where there may be some question
as to the bioavailability of such a product, the study may utilize a solution of the
drug instead of or in addition to the marketed product. The use of a solution can,
of course, result in some difficulty in interpretation of the data: a solid dosage
form, when compared to a solution, will usually exhibit a lower Cmax and a longer
tmax. The clinical significance of these differences may be difficult to assess.
In some instances, the FDA must designate a specific product as the reference
standard from among two or more possible products; e.g., Proventil tablets, 4 mg
(Schering), not Ventolin tablets 4 mg (Allen and Hanburys), is the reference
product in bioequivalence studies of albuterol sulfate conventional tablets (108).
Advantages of Multiple-
dose vs. single dose
studies:
Another important question is whether the bioequivalence trial should compare
single doses of the formulations or if it should compare "steady-state" conditions
reached after multiple dosing. It would seem that multiple dosing would be the
logical choice for drugs intended for long-term use since this would give a more
realistic comparison in view of the way in which the drug is normally adminis-
tered. Other advantages of conducting a multiple-dose study over a single-dose
study include (54, 59):
1. Multiple-dosing eliminates the long washout periods required between single-dose administra-
tions. The switch-over from one formulation to the other can take place in steady state.
2. Single-dose studies may pose problems of sufficiently long sampling periods in order to get reli-
able estimates of terminal half-life, which is needed for correct calculation of the total AUC.
3. Multiple-dose studies yield higher concentrations of drug in the blood, making accurate mea-
surement easier. In addition, since drug concentrations need to be measured only over a single
dosing interval at steady state, the need to measure lower concentrations during a disposition
phase is avoided.
4. Multiple-dosing studies can be conducted in patients, rather than healthy volunteers, allowing
the use of higher doses.
5. Usually, smaller intersubject variability is observed in steady-state studies, which may permit
the use of fewer subjects.
6. Nonlinear pharmacokinetics, if present, can be more readily detected at steady-state following
multiple-dosing.
Thus, for some drug products, multiple-dose bioequivalence studies are appropri-
ate and should be performed. In fact, according to one of the conclusions of the
Bio- International '92 conference on the bioequivalence of highly variable drugs, a
multiple-dose study is required in the case of compounds exhibiting nonlinear
pharmacokinetics (110). The circumstances under which a multiple-dose study
may be required are summarized in the regulations (109):
1. When there is a difference in the rate of absorption but not in the extent of absorption.
2. When there is excessive variability in bioavailability from subject to subject.
3. When the concentration of the active moiety in the blood resulting from a single dose is too low
for accurate determination.
4. When the drug product is a controlled-release dosage form.
On the other hand, multiple-dose bioequivalence studies are undesirable in some
respects. Healthy subjects should not be dosed with any drug for an extended
period of time (59). Multiple-dose studies are also generally more difficult to
carry out, especially with regard to ensuring subject compliance with dosing and
dietary restrictions. Therefore, most bioequivalence studies are conducted as sin-
gle-dose studies. Multiple-dose studies should be performed only when a sin-
gle-dose study is not a reliable indicator of bioavailability (111).
8.2.3 ASSESSMENT OF BIOEQUIVALENCE
In order for different formulations of the same drug substance to be considered
bioequivalent, they must be equivalent with respect to the rate and extent of drug
absorption. Thus, the two predominant issues involved in the assessment of
bioequivalence are: the pharmacokinetic parameters that best characterize the rate
and extent of absorption and, the most appropriate method of statistical analysis of
the data.
Pharmacokinetic criteria With regard to the choice of the appropriate pharmacokinetic characteristics,
Westlake suggests comparisons of the formulations should be made with respect to
only those parameter(s) of the blood level profile that possess some meaningful
relation to the therapeutic effect of the drug (107). Since the AUC is directly pro-
portional to the amount of drug absorbed, this pharmacokinetic parameter is most
commonly used to characterize the extent of absorption, both in single- and multi-
ple- dose studies.
The choice of an appropriate pharmacokinetic characteristic for the rate of absorp-
tion is still being discussed with considerable controversy (112, 113). Although a
broad array of methods exists for calculating absorption rates (e.g. moment analy-
sis, deconvolution procedures and curve-fitting), the most commonly used param-
eters are peak concentration (Cmax) and time to peak concentration (tmax).
Although these parameters have been observed to have significant variances and
may be difficult to determine accurately, they remain the parameters generally
requested as rate characteristic by most regulatory authorities for immedi-
ate-release products (112).
Statistical criteria After a bioequivalence study is conducted and the appropriate parameters are
determined, the pharmacokinetic data must be examined according to a set of pre-
determined criteria to confirm or refute the bioequivalency of the test and refer-
ence formulations. That is, one must determine whether the test and reference
products differ within a predefined level of statistical significance. Since the sta-
tistical outcome of a bioequivalence study is the primary basis of the decision for
or against therapeutic equivalence of two products, it is critically important that the
experimental data be analyzed by an appropriate statistical test.
In the early 1970s, bioequivalence was usually determined only on the basis of
mean data. Mean AUC and Cmax values for the generic product had to be within
+20% of those of the reference (innovator) product (108). Although the 20% value
was somewhat arbitrary, it was felt that for most drugs, a 20% change in the dose
would not result in significant differences in the clinical response to drugs (114).
A relatively common misconception is that current regulatory standards still allow
this difference of 20% in the means of the pharmacokinetic variables (Cmax and
AUC) of the test and reference formulations. The FDA's statistical criteria for
approval of generic drugs now requires the application of confidence limits to the
mean data, using an analysis known as the two one-sided tests procedure (115).
This change came about as a result of the conclusion of the FDA Bioequivalence
Task Force in 1986 that the use of a 90% confidence interval based on the two
one-sided t-tests approach was the best available method for evaluating bioequiva-
lence (111).
Westlake was the first to suggest the use of confidence intervals as a means of test-
ing for bioequivalence (116). Recognizing that no two products will result in iden-
tical blood-level profiles, and that there will be differences in mean values between
products, Westlake pointed out that the critical issue was to determine how large
those differences could be before doubts as to therapeutic equivalence arose (107,
117). A test formulation was considered to be bioequivalent to a reference formu-
lation if and . (119). By this proce-
dure, if test and reference products were not bioequivalent (i.e. means differed by
more than 20%), there was a 5% chance of concluding that they are bioequivalent.
The current FDA guidelines are that two formulations whose rate and extent of
absorption differ by -20%/+25% or less are generally considered bioequivalent
(90). In order to verify that the -20%/+25% rule is satisfied, the two one-sided sta-
tistical tests are carried out: one test verifies that the bioavailability of the test
product is not too low and the other to show that it is not too high. The current
practice is to carry out the two one-sided tests at the 0.05 level of significance.
Computationally, the two one-sided tests are carried out by computing a 90% con-
fidence interval. For approval of an ANDA, a generic manufacturer must show
that the 90% confidence interval for the ratio of the mean response (usually AUC
0.8
AUC
test
AUC
ref
------------------- 1.2 < < 0.8
Cp
max
t est
Cp
max
ref
-------------------- 1.2 < <
and Cmax) of its product to that of the innovator is within the limits of 0.8 to 1.25.
Since these tests are carried out at the 0.05 level of significance, there is no more
than a 5% chance that they will be approved as equivalent if they differ by as much
or more than is allowed by the equivalence criteria (-20%/+25%).
Since this test requires that the 90% confidence interval of the difference between
the means be within a range of -20%/+25%, it is more stringent than simply requir-
ing the comparison of the test and reference products' AUC and C
max
to be within
the 80 to 125% range. If the mean response of the generic product in the study
population is near 20% below or 25% above the innovator mean, one or both of the
confidence limits will fall outside the acceptable range and the product will fail the
bioequivalence test. Thus, the confidence interval requirement ensures that the
difference in mean values for AUC and C
max
will actually be less than -20%/
+25%. It should be pointed out that the standards vary among drugs and drug
classes. For example, antipsychotic agents may fall within a 30% variation and
antiarrhythmic agents may be allowed a 25% variation (122).
The actual differences between brand and generic products observed in bioequiva-
lence studies have been reported to be small. The FDA has stated that for
post-1962 drugs approved over a two-year period under the Waxman-Hatch bill
(1984), the mean bioavailability difference between the generic and pioneer prod-
ucts has been about 3.5% (120). In addition, 80% of the generic drugs approved
by the FDA between 1984 and 1986 differed from the innovator products by an
observed difference of only +5%. Such differences are small when compared to
other variables of drug therapy and would not be expected to produce clinically
observable differences in patient response.
8.2.4 CONTROVERSIES AND CONCERNS IN BIOEQUIVALENCE
The design, performance and evaluation of bioequivalence studies have received a
great deal of attention over the past decade from academia, the pharmaceutical
industry and regulatory agencies. A number of concerns and questions have been
raised about the conduct of bioequivalence studies as well as the guidelines and
criteria used to determine bioequivalence (112). Many of these concerns were trig-
gered by the passage of the Drug Price Competition and Patent Term Restoration
Act (The Waxman-Hatch Amendments) by Congress in 1984. This Act provided
for an expedited approval by the FDA of generic drugs, thereby expanding the
potential generic market for prescription generic drugs (121). Shortly after the
passage of this Act, numerous published reports appeared in the scientific litera-
ture questioning the FDA's ability to ensure that generic drugs were equivalent to
the brand name drugs they were copying. Most of the concerns of the scientific
community centered around adequate standards for evaluation of bioequivalence
and correlation between bioequivalence and therapeutic equivalence. Some of the
issues and concerns that were raised are summarized in Table 8-14 on page 32 (8,
13).
TABLE 8-14 Issues and Concerns regarding bioequivalence
At the center of the controversy were the methods and criteria used by the FDA to
determine bioequivalence. Assessment of bioequivalence was done on the basis of
mean data: mean AUC and C
max
values for the generic product had to be within
+20% of those of the innovator product for approval. A statistical test was
employed to assess the power of the test to detect a 20% mean difference in treat-
ments. For drugs that could not meet the statistical criteria because of inherent
variability, another rule was used, the so-called "75/75" rule: that in at least 75%
of the subjects, the test formulation must fall within the range of 75% to 125% of
the reference standard to be considered equivalent (122). It was felt by many that
these rules permitted too much variability in the bioavailability of test drugs and
could result in therapeutic failure or increased risk of side effects (4, 15, 123).
Statistically, the power approach and the 75/75 rule were shown to have poor per-
formance characteristics and bioequivalence evaluation based on these methods
was discontinued by the FDA in 1986. In their place, the Agency currently
employs the two one-sided tests procedure, as previously discussed.
Although the decision of bioequivalence is now made in a more statistically valid
way and the associated concerns have diminished somewhat, some important
questions and controversies in bioequivalence remain. These are primarily cen-
tered around study design, the criteria used to establish or refute equivalence, and
the assumption that products that are bioequivalent are therapeutically equivalent.
One criticism of bioequivalence testing is that it is almost always done in a panel
of young, healthy male volunteers rather than in the target population for which the
drug is intended. Clearly, the performance of a drug product in a 20-year-old male
will not be the same as in an 85-year-old woman. Serious concerns have been
Correct analysis of drugs in biological fluids
Appropriate choice of pharmacokinetic parameters to assess bioequivalence
Generalizing results obtained in healthy volunteers to patients
Problems involved in extrapolating from single-dose studies to steady-state
Importance of evaluating active metabolites
Inadequate statistical criteria to evaluate bioequivalency
Bioequivalence does not always ensure therapeutic equivalence
Lack of clear guidelines for evaluation of bioequivalence
raised that different results would be observed in elderly patients, in women, in
patients with diseases of the gastrointestinal tract, and in patients with diminished
renal or hepatic function. However, although factors such as age and disease state
might affect the actual observed concentrations of drug, the products being com-
pared should be affected in a similar fashion, and one can still be compared to the
other. If two products show an equivalent level in healthy volunteers, their levels
should be elevated to the same extent in patients with impaired hepatic function.
Thus, they can still be compared to each other. Healthy male volunteers are gener-
ally used in bioequivalence studies to assure a homogeneous study population and
to permit focus on formulation factors that might affect bioavailability. In addi-
tion, healthy subjects are more likely to remain stable during the study. The condi-
tion of actual patients might change due to the disease resulting in greater
variability in the data. The FDA does recognize the possibility that some condi-
tions could cause two products that are bioequivalent in healthy subjects to be bio-
inequivalent in certain patients and is prepared to modify its guidelines if
necessary.
A study design-related area of concern is average versus individual bioavailability.
Current procedures assess equivalence in terms of average bioavailabilities, and do
not address within-subject equivalence. In recent years, there has been increased
interest expressed in the variability of response, particularly variability within an
individual. This has given rise to the most recent controversy in bioequivalence
assessment, namely whether average bioequivalence is adequate to allow inter-
changeability of drugs in an individual (112). Anderson and Hauck believe that a
different, more stringent, notion of bioequivalence, referred to as individual
bioequivalence, is needed to provide assurance that an individual patient can be
switched from one formulation to another (124).
The second major area of controversy has focused on the criteria used to determine
bioequivalence. Implicit in the FDA guidelines is the assumption that a -20%/
+25% change in mean serum concentration of drugs can be safely tolerated. How-
ever, there is little documentation demonstrating whether 20% variation in bio-
availabilities does or does not affect the safety and efficacy of drugs. There are
certain critical therapeutic categories (Table 8-15 on page 34) in which minor fluc-
tuations in blood levels may have a substantial impact on therapeutic outcome or
toxicity (125, 126). In view of this, some scientists believe that the FDA should be
more stringent, requiring the mean values for AUC to be within 10% rather than
20%/25%. The Bioequivalence Task Force, in its 1988 report, concluded that for
certain drugs or drug classes, there is clinical evidence that may indicate a need for
tighter limits than the then-generally applied +20% rule (111). The Task Force
recommended that the Agency consider using as an "additional nonstatistical crite-
rion" a mean difference in AUC of +10%; however, this additional criterion would
not be essential to ensuring drug bioequivalence.
TABLE 8-15 Critical Therapeutic Catagories of Drugs
In general, the choice of the appropriate bioequivalence range should be done on
clinical grounds; for a drug with a narrow therapeutic range, more stringent limits
should be considered. On the other hand, the current requirements for Cmax for
some drugs may be too stringent, considering the difficulty in accurately estimat-
ing this value. For example, it has been suggested that the acceptable bioequiva-
lence range for C
max
for fast-releasing nifedipine formulations should be 70% to
130%, rather than the usual 80% to 125%. In light of this, many, including the
Pharmaceutical Research and Manufacturers of America (formerly the Pharmaceu-
tical Manufacturers Association [PMA]), feel that the FDA should repudiate its
-20%/+25% rule and develop drug-by- drug bioequivalence criteria (127).
A third source of controversy in bioequivalence is the very foundation on which
the whole concept of bioequivalence is based: the central assumption is that if two
products are shown to be bioequivalent by currently accepted standards, then they
are also therapeutically equivalent, and thus interchangeable. A number of critics
have challenged this "bioequivalence = therapeutic equivalence" equation, point-
ing out that this relationship has not been conclusively established for most drugs
(9, 13, 16, 128). These terms are, in fact, not interchangeable; bioequivalence
means that two products have basically superimposable blood level curves (within
specified limits) while therapeutic equivalence means the products produce similar
effects. There may be situations where two products have similar blood concentra-
tions, yet if the drug has a narrow therapeutic range, they may have significantly
different therapeutic effects. On the other hand, there may be products which have
widely varying blood level profiles, but exhibit very little difference in their clini-
cal effect. This might be the case for drugs with a wide therapeutic range. In addi-
tion, the therapeutic efficacy of some drugs is not necessarily related to their blood
levels, e.g., some psychoactive drugs, where the end point of drug effects is psy-
chological and behavioral response (129).
Category Example
Cardiovascular drugs
Anticonvulsants
Bronchodilating agents
Oral anticoagulants
digoxin
phenytoin
theophylline
warfarin
Williams suggests several ways that the integrity of a bioequivalence study as a
prediction of therapeutic equivalence could be assessed (104). One way involves
the performance of specific clinical studies to confirm that products shown to be
bioequivalent in healthy subjects would be bioequivalent in the patient population
as well. A second way suggested is through post-marketing surveillance of thera-
peutic response produced by different formulations of the same drug under actual
conditions of use. A third method is based on anecdotal reports. Williams points
out that none of these methods have been systematically employed to confirm cur-
rent bioequivalence methodology.
Thus, a number of problems remain in the bioequivalence process which should be
addressed. FDA scientists themselves have readily acknowledged the existence of
shortcomings in the bioequivalence testing program. However, a great deal of
progress has been made in this area in the last twenty years. The improved design
of the studies, the interpretation of the data, the increased scientific rigor of the
acceptance criteria, as well as the more rigorous auditing and inspection program
have made bioequivalence data an appropriate and valid means of approving
generic drug products.
8.2.5 GENERIC DRUGS AND PRODUCT SELECTION
Generic drug utilization has increased dramatically in the last 20 years. In 1975,
approximately 9% of all prescription drugs dispensed were generic versions (130).
This percentage rose to 20% in 1984, and 40% in 1991. It has been variously esti-
mated that the generic share of all new prescriptions will be 46% to 65% in 1995
(131-133).
This rise of generics has not gone altogether smoothly, however; the popularity of
generic drugs took a sharp downturn in 1989 when scandal rocked the generic drug
industry. This involved illegal and unethical acts by some generic drug companies
-- payoffs to FDA employees and fraudulent drug-approval test -- aimed at getting
drugs approved ahead of other firms (134-138).
Although these events did shake the confidence of pharmacists, physicians and the
public in the quality of generic drugs and cast a shadow over generics generally,
these concerns were relatively short-lived. Numerous surveys conducted one to
two years after the scandal unfolded indicated that confidence in generic drugs had
been regained and that the generic industry was in better shape with pharmacists
than it had been before the scandal occurred (139-146). Given the seriousness of
the events, the speed with which generics came back was impressive. This was
due in part to the FDA's reaction to the scandal: a multilevel reorganization of its
generic drug operations and a comprehensive inspection of the leading manufac-
turers of generic drugs (134, 140, 147, 148). It was felt that this stringent FDA
review of generics proved the overall integrity of the companies that emerged with
a clean bill of health. After a sharp drop in the use of generic drugs in 1989, they
began to rise nearly as quickly as they fell, and by mid-1990, sales of generics
were approaching their previous record high (141).
This trend in generic drug utilization is expected to continue its upward spiral, with
newly generic drugs coming to market at an increasing rate. There are several fac-
tors that have contributed to this period of considerable growth in the generic drug
industry. One major factor was the passage of the Drug Price Competition and
Patent Term Restoration Act (Waxman-Hatch Act) in 1984. This act, by eliminat-
ing the requirement for clinical safety and efficacy testing for generics of drugs
introduced after 1962, greatly expedited the entry of generic drugs into the market-
place. The purpose of this act was to facilitate generic competition and thereby
reduce health care costs. This act significantly expanded the number of drugs eli-
gible to be manufactured as generics. Another factor fueling the surge of generic
products is the abundance of brand name drugs whose patents began expiring in
1986. Between 1991 and 1994, patents expired on brand-name drugs whose com-
bined annual sales totaled $10 billion (141). These include Procardia, Ceclor,
Tagamet, Cardizem, Feldene, Naprosyn, and Xanax. All told, more than
100 drugs worth upwards of $25 billion in sales will have come off patent by the
year 2000 (149). Table 8-16 on page 37 lists some recent and impending patent
expirations (150, 151). As a result of these patent expirations on popular drugs,
there has been an explosion of new generic drug applications.
TABLE 8-16 Recent and pending patent expirations
*Extentions may be granted
Perhaps the major factor promoting generic drug utilization is the increased atten-
tion to containing health-care costs. Pushed by a drive for lower-cost medication
by federal and state governments, private insurers, corporate benefit managers,
regulatory agencies and consumer groups, generic drug usage is at a peak. Addi-
tional impetus could come from health care reform, wherein generic drugs are
viewed as a key to controlling pharmaceutical costs. Managed care programs are
expected to cover more than 70% of all outpatient prescriptions by the end of the
decade, with an accompanying greater demand for generic products (152). Thus
the demand for generic drugs will continue to rise, in a climate that favors health
care reform, lower- cost medications and broad-based prescription benefits (153).
With the increasing availability of generic drugs, pharmacists are called upon more
and more often to select a patient's drug product from a myriad of multisource
products. The pharmacist's role in product selection has increased dramatically in
the past decade and the proper selection of multisource drug products has become
a major professional responsibility of pharmacists. Although most pharmacists do
not, realistically, evaluate the bioequivalence of two products from blood level
data, professional judgement does need to be exercised; and this requires an under-
standing and application of the biopharmaceutical principles discussed.
Brand Name Generic Name Patent Expiration Date*
Procardia
Tenormin
Ceclor
Cardizem
Feldene
Naprosyn
Xanax
Tagamet
Seldane
Micronase
Capoten
Zantac
Trental
Noroxin
Nifedipine
Atenolol
Cefaclor
Diltiazem
Piroxicam
Naproxen
Alprazolam
Cimetidine
Terfenadine
Glyburide
Captopril
Ranitidine
Pentoxifylline
Norfloxacin
1991
1991
1992
1992
1992
1993
1993
1994
1994
1994
1995
1995
1997
1998
8.2.6 THE ORANGE BOOK
One of the factors that led to the widespread repeal of the state anti-substitution
laws in the 1970's was an effort by the states to contain drug costs and the estab-
lishment of maximum allowable costs (MACs) for reimbursement of drugs under
Medicaid. By allowing the pharmacist to select the manufacturer of a drug, the
less- expensive generic version could be dispensed. However, before the pharma-
cist could knowledgeably select a generic drug, he had to know which generics
were bioequivalent to the innovator product and thus, interchangeable. (There was
substantial evidence at this time that not all pharmaceutically equivalent products
were bioequivalent). To answer this need, the states began preparing either posi-
tive or negative formularies, often turning to the FDA for assistance in this under-
taking.
In response to the many requests for assistance from the states in developing their
formularies, the FDA Commissioner notified state officials of FDA's intent to pro-
vide a list of all prescription drug products that have been approved as being safe
and effective, along with therapeutic equivalence determinations for multisource
prescription products. This list, entitled Approved Drug Products with Therapeu-
tic Equivalence Evaluations, more commonly known as "The Orange Book" was
first published in 1980 and is now in its 14th edition. It is published annually and
updated monthly. The Orange book is generally considered to be the most reliable
guide for determining which drug products are therapeutically equivalent.
The Prescription Drug Products List contains:
1. all the drug products approved by the FDA as being safe and effective under the Federal Food,
Drug and Cosmetic Act, and
2. 2.the therapeutic equivalence evaluations for all approved multisource prescription drug prod-
ucts (those pharmaceutical equivalents available from more than one manufacturer).
Currently, multisource products comprise almost 80% of the approximately 10,000
drugs on the Prescription Drug Product List. The therapeutic evaluation for these
products have been prepared to serve as information and advice to state health
agencies, pharmacists and prescribers to promote knowledgeable drug product
selection and to foster containment of health costs.
8.2.7 THERAPEUTIC EQUIVALENCE
Drug products are considered to be therapeutic equivalents if they are pharmaceu-
tical equivalents and if they can be expected to have the same clinical effect when
administered to patients as specified in the labeling (90). In general, the FDA
evaluates as therapeutically equivalent those drug products that satisfy the follow-
ing general criteria:
1. They are approved as safe and effective.
2. They are pharmaceutical equivalents; i.e. they
a. contain identical amounts of the same active ingredient in the same dosage form and route
of administration, and
b. meet compendial and other applicable standards for quality, purity, strength and identity.
3. They are bioequivalent. Bioequivalence may be established by either an in-vivo or in-vitro test,
depending on the drug. If the drug presents a known or potential bioequivalence problem then
an appropriate standard must be met which demonstrates a comparable rate and extent of
absorption.
4. They are adequately labeled.
5. They are manufactured in compliance with Current Good Manufacturing Practice regulations.
The FDA believes that drug products meeting the above criteria are therapeutically
equivalent and can be substituted with the full expectation that the substituted
product will produce the same therapeutic effect as the prescribed product.
8.2.8 THERAPEUTIC EQUIVALENCE EVALUATION CODES-
The FDA uses a two-letter coding system for multisource products. The first letter
in the code allows users to determine whether a particular product has been evalu-
ated therapeutically equivalent to other pharmaceutically equivalent products. The
second letter in the code provides additional information about the basis of FDA's
evaluation. The various categories are summarized in Table 8-17 on page 40.
TABLE 8-17 Therapuetic equivalency codes
"A" Drug Products "B" Drug Products
Drug products the FDA considers to be therapeutically equivalent; i.e. drug
products for which:
1. There are no actual or potential bioequivalence problems. These are
designated as:
AA Products in conventional dosage forms
AN Solutions and powders for
aerosolization
AO Injectable oil solutions
AP Injectable aqueous solutions
AT Topical products
2. Actual or potential bioequivalence problems have been resolved via
adequate in vivo and/or in vitro tests. These are designated as AB.
Drug products the FDA does not consider to be therapeutically equivalent; i.e.
drug products for which actual or potential bioequivalence problems have not
been resolved by adequate evidence of bioequivalence. Often the problem is
with specific dosage forms rather than with the active ingredient. These products
are classified as "B" for one of three reasons:
1. The active ingredients or dosage forms have documented or potential
bioequivalence problems, and no adequate studies demonstrating
bioequivalence have been submitted.
2. The quality standards are inadequate or the FDA has insufficient
basis to determine therapeutic equivalence.
3. The drug product is under regulatory review.
These products are designated as:
BC Controlled-release tablets, capsules and injectables
BD Active ingredients and dosage forms with documented
bioequivalence problems
BE Delayed-release oral dosage forms (e.g. enteric-coated
products)
BN Products in aerosol-nebulizer drug delivery systems
BP Active ingredients and dosage forms with potential
bioequiva-
lence problems
BR Suppositories or enemas that deliver drugs for systemic
absorption
BS Products having drug standard deficiencies
BT Topical products with bioequivalence issues

BX Insufficient data to determine therapeutic equivalence
B* Drug products requiring further FDA investigation and
review to determine equivalence
There are two basic categories into which multisource drugs have been placed, "A"
or "B". Drug products rated "A" are products that the FDA considers to be thera-
peutically equivalent to the pharmaceutically equivalent original product. These
fall into one of two classes:
1. There are no known or suspected bioequivalence problems.
2. Actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in
vitro evidence supporting bioequivalence.
Category "B" consists of drug products that the FDA does not at this time consider
to be therapeutically equivalent to the pharmaceutically equivalent reference prod-
uct. Certain types of products are rated B by virtue of their specialized dosage
forms. For example, controlled-release dosage forms are rated BC, unless
bioequivalence data have been submitted as evidence of equivalence. In this case,
the product would be coded AB.
The fact that a product is in the "B" category does not mean it should not be dis-
pensed; it simply means that a B rated product should not be substituted for a phar-
maceutically equivalent product. For example, glyburide is marketed as
Micronase and DiaBeta by two different manufacturers. Both these products
are clinically effective, but because bioequivalence between the two has not been
studied, they are B rated and are not interchangeable.
To avoid possible significant variations among generic drugs as a result of compar-
ison to different reference drugs, the FDA began designating a single reference
listed drug against which all generic versions must be shown to be bioequivalent.
The reference listed drug is identified by the symbol "+" in the Prescription Drug
Product List. This symbol was used for the first time in the 1993 edition of the
Orange Book.
Limitations and
exclusions-
Although the Orange Book is a very valuable reference for pharmacists perform-
ing drug product selection, it has certain limitations, which must be recognized. It
was not intended to serve as a single comprehensive reference on all multisource
drugs. Many prescription drug products are not listed in the Orange Book, making
evaluation of their therapeutic equivalence difficult, if not impossible. Exclusion
of a drug from the Orange Book means that the FDA has not evaluated its safety,
efficacy and quality. Table 18 lists the classes of products excluded from the
Orange Book. Because the equivalence of these excluded products is unknown,
interchanging of these products should be avoided.
TABLE 8-18 Drug Products excluded from the Orange Book
Another limitation of the Orange Book that all pharmacists should be aware of is
that the drug listings contain the names of only the companies that actually hold an
approved NDA or ANDA; they may not be the same as the actual manufacturer or
distributor. It is fairly common practice for a drug to be manufactured pursuant to
an NDA or an ANDA but distributed under license agreement by another com-
pany. In this instance, the distributor would not be listed in the Orange Book.
Since pharmacists are, understandably, generally unaware of the name of the actual
holder of the NDA or ANDA, it is often difficult for them to determine the thera-
peutic equivalence of a particular multisource product if it is not listed in the
Orange Book. For example, there are over thirty manufacturers and distributors
marketing approved, therapeutically equivalent versions of furosemide 40 mg tab-
lets (154). However, only twelve of these companies are actually listed in the
Orange book, since these are the actual holders of an NDA or ANDA. Therefore,
the pharmacist would have to verify the therapeutic equivalence evaluation of the
non-listed products by obtaining the information from the manufacturer, packager,
or supplier.
Legal status and
pharmacists'
responsibility-
The Orange Book per se has no legal status. The FDA stresses that it is a source of
information and advice on drug product selection, but it does not mandate the drug
products which may be dispensed nor the products that should be avoided. Thus,
the Orange Book does not carry the weight of regulation or law, and the FDA
assumes no liability for drug products selected on the basis of its equivalence eval-
uation.
The Orange Book points out that "FDA evaluation of therapeutic equivalence in no
way relieves practitioners of their professional responsibilities in prescribing and
dispensing such products with due care." There are circumstances where pharma-
1. Drugs marketed before the passage of the Federal Food, Drug, and Cosmetic Act of 1938. These are not
included because the FDA has not reviewed these drugs for safety and efficacy and does not have the necessary
information to make therapeutic equivalence evaluations.
Examples: digoxin, morphine, codeine, thyroid, levothyroxine, phenobarbital and nitroglycerin
2. Drugs for which the FDA has no NDA or ANDA on file.
Examples: Anusol-HC, Naldecon (and their generic counterparts)
3. Drugs still undergoing Drug Efficacy Study Implementation (DESI) review. These are drugs that were
marketed between 1938 and 1962 on the basis of safety, but not efficacy. Although most of these drugs have
been reviewed and are listed in the Orange Book, there are still a number of these pre-1962 drugs which have
not yet been classified as "effective" under the DESI program, and are not listed.
Examples: nitroglycerin controlled-release capsules, pentaerythritol tetranitrate, isocarboxazid,
hydrocortisone-iodochlorhydroxyquin cream
In addition, nitroglycerin transdermal patches are still undergoing efficacy studies, and are not listed in the
Orange Book.
cists will have to exercise professional care and sound judgement in selecting a
drug product for a particular patient. Although two products may be rated as being
therapeutically equivalent in the Orange Book, they may not be equally suitable
for a particular patient. Drugs that share the "A" code may still vary in ways that
could affect patient acceptance. They may differ in shape, color, taste, scoring,
configuration, packaging, preservatives, expiration time, and in some instances,
labeling. If products with such differences are substituted for each other, there is
potential for patient confusion or decreased patient acceptance. For example, a
patient may be sensitive to an inert ingredient in one product that another product
does not contain. Or, a patient may become confused if the color or shape of a
product varies from that to which he has become accustomed. A patient may reject
the administration of a substituted product because of differences in taste or
appearance. When such characteristics of a specific product are important in the
treatment of a particular patient, the pharmacist should select a product with these
considerations in mind as well as bioequivalence.
Despite its limitations and shortcomings, the Orange Book is a very useful guide
for rational product selection. Pharmacists can utilize the information presented
there, in combination with sound professional judgment, to make decisions on
behalf of their patients regarding the choice of the most appropriate drug product.
8.3 Drug Product Selection
Multisource drug product selection has become a very important component of
contemporary pharmacy practice. The National Prescription Audit (NPA) has, for
some years now, been chronicling the heightened role played by pharmacists in the
selection of which brand (or generic version) of a multiple-source drug will be dis-
pensed to the patient. From 1983 through 1993, the pharmacist's role in selecting
brand or generic products for dispensing has increased dramatically, as shown in
Table 19. In the first half of 1993, pharmacists controlled 41% of dispensing deci-
sions, as compared to 16% in 1983. It is evident that the substitution trend is
strong and is continuing to gain ground. This expansion of pharmacy's province in
brand choice decisions is the result of several factors: economic pressures for
lower prescription costs, repeal of anti- substitution laws and increased acceptance
of generics by patients, physicians and pharmacists. Perhaps the most significant
factor in escalating the overall level of pharmacists' brand choice decisions has
been the expiration of the patents of high- volume pioneer brands, as previously
discussed. This has resulted in significant expansion in the potential for pharma-
cist choice.
TABLE 8-19 Pharmacists Brand Selection
Year Percent of all new prescriptions involving
pharmacists brand choice
a
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
Jan.-June 1993
16
18
20
23
25
27
30
32
34
38
41
8.3.1 CONSIDERATIONS IN SELECTING A MANUFACTURER
The selection of a pharmaceutical manufacturer of a multisource product has
become an important professional responsibility for pharmacists. This responsibil-
ity has become an especially critical part of a pharmacists role in light of the
increasing number of generic products available and in light of some of the prob-
lems that have occurred in the generic drug industry (the "generic drug scandal" of
1989). The pharmacist is entrusted by the public to select manufacturers that offer
the best quality at the best price.
So how does the phar-
macist select the manu-
facturer of a multisource
drug product? What
factors should be con-
sidered?
Thoughtful selection of a multisource drug product is not an easy task, and
requires a consideration of not only the drug product itself, but also the manufac-
turer, and in some cases, the patient. Several options are open to the pharmacist
performing drug product selection: to select a product solely on the basis of eco-
nomics, to select a product on the basis of the reputation of the manufacturer, or to
make a decision based on product bioequivalence and quality and on the basis of
the product's conformity with official compendial standards and with those estab-
lished by the FDA. The first option, while offering a financial advantage, does not
provide assurance of therapeutic efficacy. The second option, although subjective,
is easily applied and does offer a degree of security to the pharmacist. The third
option is the most challenging to the pharmacists, requiring the application of prin-
ciples of biopharmaceutics and pharmacokinetics in arriving at a decision. Ideally,
the pharmacist should take into consideration all the above options when selecting
a drug product for a patient.
When pharmacists were asked which factors are most important to them in select-
ing a manufacturer of a generic product, the primary criteria indicated were the
reputation and quality of the company (159-162). Bioequivalence to the
brand-name product was also ranked as being an important factor in product selec-
tion. However, the most frequently used sources for assessing bioequivalence
were manufacturer reputations (based previous experience) and product literature
provided by the distributing company. Company-sponsored material must be care-
fully evaluated. Unfortunately, promotional literature does not generally contain
sufficient data to permit rational analysis of whether or not products are bioequiva-
lent (163). Also, relying on personal methods of information gathering for assess-
ing bioequivalence is not very reliable. Interestingly, only 23% of pharmacists
reported using the Orange Book in assessing bioequivalence (161). Selection of
drug products should be based on sound scientific and clinical grounds. Develop-
ments in the science of pharmacokinetics and the related area of bioavailability
have given pharmacists the tools necessary to make sound choices among multi-
source products. In response to the profession's need for information and advice
on how to select appropriate drug products from multiple sources, the American
Pharmaceutical Association formed a Bioequivalency Working Group to establish
guidelines for product selection (Table 8-20 on page 47) (164). This Group made
recommendations of factors that pharmacists should consider when selecting drug
products to be dispensed to their patients. If pharmacists consider the factors indi-
cated as part of the professional judgement process when making drug product
selections, it is likely that the best interest of the patients will be served.
The appropriate selection of a generic drug product involves much more than just
cost considerations or reliance on state and federal laws and regulations. It
requires a knowledge of the drug entity and its physical and chemical properties,
the condition to be treated, and its significance, and the history and attitude of the
manufacturer. One of the criteria often used to evaluate a manufacturer's record is
the number and type of recalls of that company's products. Product selection may
also require taking into consideration the patient, the disease, previous drug ther-
apy, and duration of therapy before a decision is made. Gagnon presented a
step-by-step analysis procedure that pharmacists can use in evaluating multisource
suppliers of a pharmaceutical product (Table 8-21 on page 49) (165). Using this
procedure, each manufacturer is rated in each area listed, thus enabling the phar-
macist to make the most rational choice.
TABLE 8-20 Guidelines for product selection
DISPENSING DECISIONS
? State Rules and Regulations. Pharmacists should be cognizant of legal requirements that address the issue of drug product selection. Many states have positive or negative
formularies to provide guidance in drug product selection.
? Bioequivalency Information/Orange Book Ratings. Only products with proven bioequivalency should be selected to be dispensed in lieu of the innovator product.
Products that are listed in the FDA's Approved Drug Products and Therapeutic Equivalence Evaluations (the Orange Book) as "A" rated should be selected when such products
are available. For pre-1938 drugs, the selection should be based on data obtained from the literature, because bioequivalency testing is not required by the FDA for these
drug products.
? Dosage Form. The type of dosage form should be considered whenever one drug product is selected from among multisource drug products. This is especially true with
extended or delayed release medications.
? Previous Drug Use. Two questions should be considered regarding previous drug product usage. First, is the prescribed drug a continuation of already successful therapy?
If it is, the impact of any change in source of the medication should be considered. The pharmacist should also know which product the patient was using previously, including
any medications in the hospital if the patient was recently discharged. Second, was the original product dispensed a generic product? If so, preference should be given to
continuing to dispense the same generic product from the same source.
? Patient Status. The pharmacist should consider how well controlled the patient is and how susceptible that patient might be to small changes in drug absorption. If a
patient has labile control or has experienced great difficulty in achieving control, the pharmacist should continue therapy with a product from a single source throughout therapy.
? Diseases. The seriousness of the disease and its potential impact on the patient may influence the pharmacist's willingness to change products.
? Drug Class or Category. Drugs with narrow therapeutic ranges and with known clinically significant bioavailability problems should be substituted with care and/or after
discussion with the prescriber.
? Cost. The cost of the product , while an important consideration, should be a secondary consideration in selecting among products judged by the pharmacist to be
bioequivalent.
? Patient Opinion. An informed patient, cooperating with a physician and pharmacist in his or her drug therapy, is an important element in ensuring the best possible
therapeutic outcomes. The pharmacist should take into account the patient's need when selecting from multisource drug products and inform the patient of any potential
consequences associated with alternate product selections.
PURCHASE DECISIONS
? Current State Laws and Regulations. Some states have positive or negative formulary systems that place regulatory restrictions on the products considered therapeutically
equivalent. The state formulary may not always be in agreement with classifications listed in the FDA's Orange Book. Therefore, pharmacists should be familiar with both.
? Bioequivalency Information/Orange Book. Products shown to be bioequivalent through reference to the Orange Book or other reliable source of bioequivalency
information are preferred. Purchase decisions for drugs marketed prior to 1938 should be based on data obtained from the literature or the manufacturer, because bioequivalency
testing may not be required by the FDA for these drug products.
? Drug Category. Greater attention should be given to purchasing strategies for drug products used for serious or life-threatening diseases and in situations where therapeutic
activity of the product is confined to a narrow range of biologic fluid concentration.
? Availability. A continuous supply from the same manufacturer is essential even in the event that the distributor has changed to ensure that refills of prescriptions will
contain the same product as originally dispensed. However, in those instances when the manufacturer of a generic drug product has to be changed, care should be exercised
to ensure that the new drug product is equivalent to the formerly stocked drug product.
? Supplier's Reputation. The reputation of the manufacturer in terms of its ability to adhere to good manufacturing practices (GMP) that ensure that each dosage form is
manufactured correctly and in a consistent manner is an important consideration. When purchasing a product from a distributor rather than directly from the manufacturer,
the procedure used by that supplier in selecting manufacturers for multisource products is also an important consideration. Establishment Inspection Reports and recall
reports are available from FDA through a Freedom of Information (FOI) request. These are valuable tools in this decision.
? Cost.
TABLE 8-21 Evaluation of Multi-source Suppliers
Factors and Cues
Product Information
Size(s) available
Dosage form(s) available
Bioequivalence data results using Orange Book
Existence of identification codes on solid dosage forms
Average number of months between product receipt and expiration date
Results of cost-effectiveness information from manufacturer
Complete product literature provided from manufacturer
Strength(s) available
State/federal formulary rules, e.g., MAC limits
Economics
Price(s)
Deals and other discounts
Terms of sale
Clear and equitable pricing policy
Large sizes available at discount prices
Product Quality
NDA/ANDA on file at FDA
Pharmaceutical elegance of products, e.g., broken tablets, powder in bottles
Less than 3 year FDA on-site inspection
Results of on-site FDA inspection
Company willing to allow pharmacist to inspect plant
Results of quality control analysis
Company willing to supply samples for testing
Product acceptance by physicians
Product acceptance by patients
Service Quality
Returns policy
Rapid resolution of complaints
Company product availability record
Liability protection policy
Terms of unconditional guarantee
Company commitment to education of practitioners
Availability of company representative
Existence of 24-hour emergency customer service telephone number
Product availability through wholesalers
Ease of placing orders
Company customer information center, including an 800 number
Company Reputation
Number of recalls in last 3 years
Severity of recalls in last 3 years
Who initiated recalls (FDA or company)
Company has a recall strategy
Other regulatory actions against company
Company has wide product line
FDA quality assurance profile
Company has crisis communication strategy
Pharmacists have the responsibility of correctly selecting and dispensing multi-
source products that will have the greatest likelihood of achieving a positive thera-
peutic outcome in a cost-effective manner. The more information pharmacists
have about a product and its manufacturer, the more likely they will be to make the
most appropriate choice. Price cannot be the single factor in selecting a product. It
is also clear, as Joseph Oddis stated, "Rational drug product selection entails far
more than simply consulting the FDA's Orange Book or looking at the price cata-
logue" (166).
8.3.2 SPECIAL CASES
While in most situations selection of drug products that are therapeutically equiva-
lent can be done without undue complications, there are some circumstances
where problems could occur. Depending on the drug, its formulation, the disease
being treated, and the condition of the patient, generic substitution may not be
advisable. Some of these special situations require extra attention and handling by
the pharmacist.
There are a number of drugs that could present problems when interchanged.
Drugs that are poorly water soluble may have inherent problems with rate and
extent of dissolution, resulting in poor or variable bioavailability. Drugs that are
potent and thus present in very low amounts in a dosage form could present prob-
lems due to formulation factors. Some dosage forms may have inherent bioavail-
ability problems, such as controlled-release products. And drugs which are
considered "critical" also need special consideration. "Critical" drugs have been
defined as drugs with a narrow therapeutic range, where a change in plasma con-
centration might result in adverse clinical outcome; drugs that are considered pri-
marily for control of a disease rather than for alleviation of temporary symptoms;
and drugs that have inherent or historical bioavailability or bioequivalence prob-
lems (8, 19). Seven classes of drugs have been identified that have demonstrated
bioequivalence problems or, because of the nature of the product, have the poten-
tial for creating therapeutic problems if product interchange is permitted (Table 8-
22 on page 51) (167-168).
TABLE 8-22 Catagories of drugs with demonstrated bioequivalence problems
There have been numerous reports of drugs implicated in therapeutic problems due
to bioinequivalence difficulties. In addition to those in the categories given in
Table 8-22 on page 51, these include furosemide, propranolol, diazepam, pred-
nisone, nitrofurantoin, and amitriptyline (20, 126, 167, 169-180). Although the
documentation implicating these drugs in therapeutic failures due to bioavailabil-
ity problems is primarily anecdotal in nature (and thus disregarded by the FDA),
the performance of these products should still be closely observed and monitored,
and care should be taken when selecting drugs from these categories.
In addition to "critical" drugs, critical patients and critical diseases have also been
identified when special care should be taken in performing product selection (8,
166). Critical patients are the very old and the very young, those suffering from
multiple diseases who are managed with multiple drugs, and those who live alone,
making observation of adverse drug effects unlikely. Critical diseases are gener-
ally chronic in nature and difficult to stabilize, where drug-disease interactions can
present major problems (e.g. congestive heart failure, asthma, diabetes, cardiac
disorders, and psychoses). In all the above special "critical" circumstances, there
is a high risk of therapeutic problems, and product selection requires extra atten-
tion and precautions. In fact, product substitution and interchange in these cases is
generally discouraged. Once a product (brand or generic) has been selected for a
course of therapy, the pharmacist should not change to a different product if it can
be avoided. If interchange is performed, it should be done only with the utmost
care, and the patient should be monitored for any adverse outcomes.
Digitalis glycosides
- digoxin
Warfarin anticoagulants
Theophylline products
Thyroid preparations (including levothyroxine)
Conjugated and esterified estrogens
Antiarrhythmic agents
- quinidine salts
- procainamide
Anticonvulsants
- phenytoin
- carbamazepine
- primidone
Pharmacist's
professional
responsibility-
Drug product selection has been and continues to be a primary and chal-
lenging professional responsibility of pharmacists. It is one where the pharmacist
must exercise professional care and sound judgement to make decisions on behalf
of the patient to maximize safety and efficacy, while minimizing cost. Pharmacists
have a professional obligation to patients to take whatever steps are necessary to
assure themselves that the medicines they are dispensing are safe and effective.
Although some of this activity is currently constrained by bureaucratic and regula-
tory restrictions that often discourage, or entirely prevent, individual professional
evaluation and initiative, with a greater appreciation and understanding of the sci-
entific, clinical, and regulatory issues that form the basis of the process, pharma-
cists can make decisions that result in better patient care. Pharmacists must take
steps to ensure the quality and integrity of the drug products dispensed to their
patients. To accomplish this, pharmacists must look to pharmaceutical manufac-
turers to supply them with a quality product they can trust. Thus, the manufacturer
of a multisource product must be carefully selected to ensure that the products they
supply are of proper quality. If necessary, pharmacists should conduct independent
research into the reputation and integrity of the manufacturer, or, if products are
purchased through a buying group, should make sure that established policies and
guidelines are in place to review multisource products. When considering pur-
chasing drug products, the pharmacist should request the manufacturer to provide
certain documentation and information, and should then evaluate this information
(see Table 23).
TABLE 8-23 Considerations when evaluating a Multi-Source vendor
And finally, pharmacists can counsel the patients on the importance of
using the same drug product throughout a course of therapy, even though they
might go to a different pharmacy. To further emphasize this, it has been suggested
that the initial prescription and subsequent refills of a drug product considered
questionable for interchange should contain auxiliary labeling that stresses the
importance of continuing to use that product (167).
Drug product selection is an important professional responsibility, but it is
not an easy task. It requires the pharmacist to use his/her current knowledge, and
1.Willingness to supply requested information
2.Bioavailability and bioequivalence data
3.Dissolution testing results
4.FDA bioequivalence rating
5.The actual manufacturer of the product, if not the supplier
6.FDA inspection reports
7.History of the manufacturer's recall record
8.Willingness of the manufacturer to permit on-site visitations
9.Evaluate economic considerations such as price, shipping, terms, discounts, insurance, return policies, and packagng.
all the currently available information in order to arrive at and render a decision
regarding the most appropriate product to use for a specific patient.
8.4 Summary
With the dramatic increase in the availability and utilization of generic drug prod-
ucts in recent years, pharmacists are being faced with an ever-increasing array of
multisource products. Appropriate selection of a product from the plethora of
products on the market is not always an easy task; the quality of the drug product
must be considered, as well as the cost. The principles of biopharmaceutics indi-
cate that the formulation and method of manufacture of a drug product can have a
marked effect on the bioavailability of the active ingredient. Thus, generic equiva-
lents may not necessarily be therapeutically equivalent. Guidelines and criteria
have been established by the FDA to help judge whether one product can be sub-
stituted for another with assurance of equivalent therapeutic effect.
For pharmacists to provide informed product selection, it is essential that
they be knowledgeable about, and familiar with, these guidelines and criteria. This
requires an understanding of bioavailability, bioequivalence, and how they are
determined. The pharmacist can serve a major role in ensuring that only high qual-
ity products are dispensed, and in this way help reduce health care costs without
compromising quality of care.
Acknowledgment The author gratefully acknowledges the assistance of Umesh V. Banakar in the
preparation of this manuscript.
8.4.1 QUESTIONS
1. The term bioavailability refers to the
a. dissolution of a drug in the gastrointestinal tract.
b. amount of drug destroyed in the liver by first-pass metabolism.
c. distribution of drug to the body tissues over time.
d. relationship between the physical and chemical properties of a drug and its systemic
absorption.
e. measurement of the rate and amount of drug that reaches the systemic circulation.
2. The bioavailability of various drug products can be evaluated by comparing their plasma con-
centration-time curves. The three most important parameters of comparison that can be
obtained directly from the curves are
a. biologic half-life (t
1/2
), absorption rate constant, area under the curve (AUC).
b. time of peak concentration (t
max
), absorption rate constant, elimination rate constant.
c. maximum drug concentration (C
max
), time of peak concentration (t
max
), duration of action.
d. area under the curve (AUC), time of peak concentration (t
max
), maximum drug concentration
(C
max
).
e. rate of elimination, area under the curve (AUC), rate of absorption.
3. Two products are bioequivalent if they
a. contain the same amount of the same active ingredient.
b. have equal areas under the curve after the administration of the same dose.
c. have the same value for C
max
after administration of the same dose.
d. have equivalent rates and extents of absorption of the drug after administration of equal
doses.
e. are pharmaceutically equivalent.
4. If an oral capsule formulation of drug A produces a plasma concentration- time curve having
the same area under the curve (AUC) as that produced by an equivalent dose of drug A given
intravenously, it can generally be concluded that:
a. there is no advantage to the IV route.
b. the absolute bioavailability of the capsule formulation is equal to 1.
c. the capsule formulation is essentially completely absorbed.
d. the drug is very rapidly absorbed.
e. b and c are correct.
5. 5.Which of the following is NOT a criterion for therapeutic equivalence of two products,
according to the FDA?
a. They must be pharmaceutical equivalents.
b. All ingredients - active and inactive - must be the same.
c. They have been manufactured in compliance with Good Manufacturing Practices.
d. They are bioequivalent.
e. They are approved as safe and effective by the FDA.
6. A test oral formulation has the same area under the plasma concentration- time curve as the ref-
erence formulation. This means that the two formulations
a. are bioequivalent by definition.
b. deliver the same total amount of drug to the body but are not necessarily bioequivalent.
c. are bioequivalent if they both meet USP dissolution standards.
d. deliver the same total amount of drug to the body and are, therefore, bioequivalent.
e. have the same rate of absorption.
7. In-vitro dissolution rate studies on drug products are useful in bioavailability evaluations only if
they can be correlated with
a. in-vivo bioavailability studies in humans.
b. the chemical stability of the drug.
c. USP disintegration requirements.
d. in-vivo studies in at least three species of animals.
e. the therapeutic response observed in patients.
8. Which of the following statements regarding bioequivalence is TRUE?
a. If the mean AUC and C
max
values for a generic product are within + 20% of those of the ref-
erence product, the two products are bioequivalent.
b. If we can be 90% certain that the mean values of AUC and C
max
for two products are within
80% to 125% of each other, then the two products are considered bioequivalent.
c. Bioequivalence studies are generally conducted in a panel of patients consisting of the tar-
get population for which the drug is intended.
d. Bioequivalence studies are generally conducted as multiple-dose studies utilizing the
cross-over design.
e. If two products are shown to be bioequivalent, we can always say with certainty that they
will be therapeutically equivalent.
9. 9.Which of the following statements about the FDA Orange Book is TRUE?
a. Drugs that are excluded from the Orange Book are not safe and effective and should not be
dispensed.
b. It contains therapeutic equivalence evaluations for all the drugs approved by the FDA.
c. Products placed in the "B" category should not be dispensed.
d. The Orange Book is an official compendium, and pharmacists can legally only dispense
those products listed as bioequivalent.
e. The drug listings contain the names of only the companies that actually hold an approved
NDA or ANDA for a drug.
10. 10.Growth in the utilization of generic drug products can be attributed to
a. passage of the 1984 Waxman-Hatch Act.
b. expiration of patents of many popular brand products.
c. pressures to reduce health care costs.
d. the growth of managed health care organizations.
e. all of the above.
8.4.2 ANSWERS TO QUESTIONS
1. e
2. d
3. d
4. e
5. b
6. b
7. a
8. b
9. e
10. e
8.5 Bioavailibility Equations
The following set of equations were used to solve the bioavailability problem set.
The problem sets for the first two drugs have been done for you. The others are
done exactly the same way. The answers follow the problems.
1. as discussed in chapter 4.
2.
3.
4.
5.
6.
7.
8. as discussed in chapter 4
9.
10.
11.
MRT
iv
AUMC
iv
AUC
iv
--------------------- =
k
1
MRT
iv
---------------- =
t
1 2
2 ln
k
-------- =
Cp
0iv
AUC k =
V
d
Dose
iv
Cp
0
iv
----------------- =
Cp
iv
Cp
0
e
kt
=
f
AUC
oral
Dose
oral
---------------------
Dose
iv
AUC
iv
----------------- =
MRT
po
AUMC
po
AUC
po
----------------------- =
MAT
po
MRT
po
MRT
iv
=
k
a
1
MAT
------------ =
t
p
k
a
k
-----
,
_
ln
k
a
k
---------------- =
12.
14. Relative Bioavailability (R.B. or C.B.) =
15. Bioequivalent: Yes if all three:
Cp
max
fD
V
------
k
a
k
a
k
------------- e
kt
p
e
k
a
t
p
( ) =
AUC
generic
( ) Dose
generic
( )
AUC
Brand
( ) Dose
Brand
( )
----------------------------------------------------------------------
0.80 CB 1.25 < <
0.80
t
p
generic
t
p
brand
-------------- 1.25 < <
0.80
C
p
max g eneric
C
p
max b rand
------------------------ 1.25 < <
8.6 Problems
Aramaki, S., et al., "Pharmacokinetics of caffeine and its metabolites in horses after intravenous, intramuscular, or oral adminis-
tration", Chem Pharm Bull, Vol. 30, No. 11, (1991), p. 2999 - 3002.
This study deals with the pharmacokinetics of caffeine. Caffeine doses of 2.5 mg/kg were administered both intrave-
nously and orally to horses with an average weight of about 500 kg. A summary of the some of data obtained from this
experiment is given below. Fill in the empty cells.
TABLE 8-24 Caffeine
Dose (mg/kg) 2.5 2.5 2.5 2.5
AUC
63.1 60.7 60 57
AUMC
1442 1556.8 1600 1723
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
Cefetamet Pivoxil (Problem 8 - 2)
Ducharme, M., et. al., "Bioavailability of syrup and tablet formulations of cefetamet pivoxil", Antimicrobial Agents and Chemo-
therapy, Vol. 37, No. 12, (1993), p. 2706 - 2709.
Cefetamet pivoxil is a prodrug of cefetamet. This study compares the bioavailability of cefetamet pivoxil in tablet
form versus syrup form. A summary of the some of data obtained from this experiment is given below. Fill in the
approprate cells.
.
Dose (mg) 250 500 500 500
AUC
30.64 53.68 50 47
AUMC
101.66 191.64 205.6 225.3
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
Cefixime (Problem 8 - 3)
Faulkner, R. ,et al., "Absolute bioavailability of cefixime in man", Journal of Clinical Pharmacology, Vol. 28 (1988), p. 700 - 706.
Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram nega-
tive bacteria. In this study, sixteen subjects each received a 200 mg intravenous dose and then a 200 mg capsule with a
washout period between the administration of each dosage form. A summary of the some of data obtained from this
experiment is given below.
Parameter IV Brand Capsule Generic Capsule Bioequivalence
Dose (mg) 200 200 200
AUC
47 23.6 20.2
AUMC
183.3 162.8 187.5
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
Ceftibuten (Problem 8 - 4)
"The pharmacokinetics of ceftibuten in humans"
Ceftibuten is a new oral cephalosporin with potent activity against enterobacteriaceae and certain gram posi-
tive organisms. In this study two groups received either a 400 mg oral dosage form of ceftibuten or a 200 mg iv bolus
dose of ceftibuten. A summary of the some of data obtained from this experiment is given below.
Dose (mg) 200 400 400 400
AUC
75.2 65.9 64.2 64
AUMC
211.2 213.4 220 208
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
Cimetidine (Problem 8 - 5)
Sandborn, W., et al., "Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients", Jour-
nal of Clinical Pharmacology, Vol. 30, (1990), p. 568 - 571.
Cimetidine is a histamine receptor antagonist which is used in the treatment of gastric and duodenal ulcer dis-
ease. In this study, patients received 300 mg of cimetidine as an iv bolus on the first day and data was collected. On
the second day, the patients received 300 mg orally and data was collected. A summary of the some of data obtained
from this experiment is given below.
Parameter IV Brand Tablet Generic Tablet Bioequivalence
Dose (mg) 300 300 300
AUC
3.81 2.48 2.50
AUMC
5.33 11.73 10.73
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
Diurnal Variability in Theophylline Bioavailability (Problem 8 - 6)
Bauer, L., Gibaldi, M., and Vestal, R., "Influence of pharmacokinetic diurnal variation on bioavailability estimates", Clinical Phar-
macokinetics, vol. 9, (1984), p. 184 - 187.
This article discusses the effects of diurnal variation on the bioavailability and clearance of theophylline. In
this study patients received a 500 mg dose every 12 hours either orally or by iv bolus. A summary of the some of data
obtained from this experiment for the time period between midnight and noon is given below.
Dose (mg) 500 500 500 500
AUC
160.25 144.58 140 144
AUMC
1821 1662 1785 1700
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
cis-5-Fluoro-1-[2-Hydroxymethyl-1,3-Oxathiolan-5-yl] Cytosine
(FTC) (Problem 8 - 7)
Frick, L. , et al., "Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-Fluoro-1-[2-Hydroxyme-
thyl-1,3-Oxathiolan-5-yl] Cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus", Anti-
microbial Agents and Chemotherapy, Vol. 37, No. 11, (1993), p. 2285 - 2292.
FTC is a 2',3'-didoexynucleoside analog that may be useful against HIV and HBV. In this study, rats with an
average weight of 270 g were given either iv or oral doses of 100 mg/kg. A summary of the some of data obtained
Dose (mg/kg) 100 100 100
AUC
265 168 175
AUMC
19514 12600 13125
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
Hydromorphone (Problem 8 - 8)
Vallner, J., et al., "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to
human subjects", Journal of Clinical Pharmacology, Vol. 21, (1981), p. 152 - 156.
Hydromorphone hydrochloride is an analog of morphine which has about seven times the effect of morphine
when given intravenously. In this study, volunteers were given a 2 mg intravenous dose and a 4 mg oral dose of hydro-
morphone on separate days. A summary of the some of data obtained from this experiment is given below.
Dose (mg) 2 4 4
AUC
83 87.2 96
AUMC
289.4 401 432
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
L
------ hr
,
_
ug
L
------ hr
2
,
_
ug
L
------
,
_
ug
L
------
,
_
ug
L
------
,
_
Isosorbide Dinitrate (Problem 8 - 9)
Straehl, P. and Galeazzi, R., "Isosorbide dinitrate bioavailability , kinetics, and metabolism", Clinical Pharmacology and Thera-
peutics, Vol. 38m (1985), p. 140 - 149.
Isosorbide dinitrate is used in the treatment of angina pectoris, vasospastic angina, and congestive heart failure.
In this study volunteers received a 5 mg intravenous dose given over 5 minutes and a 10 mg tablet. The different dos-
age forms were separated by a washout period. A summary of the some of data obtained from this experiment is given
below.
Dose (mg/kg) 5 10 10
AUC
370.3 158 165
AUMC
487 310 305
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
L
------ hr
,
_
ug
L
------ hr
2
,
_
ug
L
------
,
_
ug
L
------
,
_
ug
L
------
,
_
Ketanserin (Problem 8 - 10)
Kurowski, M., "Bioavailability and pharmacokinetics of ketanserin in elderly subjects", Journal of Clinical Pharmacology, Vol. 28,
(1988), p. 700 - 706.
Ketanserin is a 5-hydroxytryptamine S2-antagonist. This study focuses on the kinetics of Ketanserin in the
elderly. Subjects were given either a 10 mg intravenous dose or a 40 mg oral tablet. A summary of the some of data
obtained from this experiment is given below.
Dose (mg) 10 40 40
AUC
247 520 400
AUMC
3991 8922 8922
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
Methotrexate (Problem 8 - 11)
Seideman, P., et al., " The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis",
British Journal of Clinical Pharmacology, 35 (1993), p. 409 - 412.
The drug Methotrexate is a folic acid which has been shown to inhibit dihydrofolate reductase. The impor-
tance of this drug at present is mostly seen in the area of oncology, but lately it has been used for rheumatoid arthritis.
Methotrexate has a molecular weight of 454.4. In this study, the drug was administered both by IV bolus and orally as
a 15 mg dose. The following data was obtained:
Dose (mg) 15 15 15
AUC
2752 2708 2700
AUMC
15887 18400 18500
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
nmole
L
---------------- hr
,
_
nmole
L
---------------- hr
2
,
_
nmole
L
----------------
,
_
nmole
L
----------------
,
_
nmole
L
----------------
,
_
Moclobemide (Problem 8 - 12)
Schoerlin, M. et al., "Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function", Jour-
nal of Clinical Pharmacology, Vol. 30 (1991), p. 272 - 284.
Moclobemide is an antidepressant agent that reversibly inhibits the A-isozyme of the monoamine oxidase
enzyme system. In this study, single IV and oral doses were administered to a patient. A summary of the some of data
Dose (mg) 150 100 100
AUC
2.58 1.70 1.52
AUMC
6.35 5.91 5.90
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
Nalbuphine (Problem 8 - 13)
Nalbuphine hydrochloride is an agonist-antagonist opiod which is used for its analgesic actions. In this study,
volunteers were given single doses of four different nalbuphine forms. The data below focuses on a 10 mg iv dose and
a 45 mg dose of an oral solution. A summary of the some of data obtained from this experiment is given below.
Dose (mg) 10 45 40 40
AUC
86.9 70.3 62.5 60
AUMC
288 306 280 270
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
Nefazodone (Problem 8 - 14)
Shukla, U. et al., "Pharmacokinetics, absolute bioavailability, and disposition of nefazodone in the dog", Drug Metabolism and
Disposition, Vol. 21, No. 3, (1993), p. 502 - 507.
Nefazodone was given to four healthy, adult, male beagles with an average weight of 11.0 kg. Each dog was
given a 10 mg/kg dose as a either a intravenous injection or as an oral solution or tablet. A summary of the some of
data obtained from this experiment is given below.
Dose (mg/kg) 10 10 10 10
AUC
6023 829 800 700
AUMC
29283 4875 4800 4500
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
Ondansetron (Problem 8 - 15)
Colthup, P., et al., "Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly", Journal of Phar-
maceutical Sciences, Vol. 80, No. 9(1991), p. 868 - 871.
Ondansetron is a 5-hydroxyltryptamine compound which is useful in treating the nausea and vomiting which is
caused by the use of chemotherapy and radiation in the cancer patients. In order to determine the absolute bioavailabil-
ity of oral Ondansetron, doses of 8 mg were given to two groups. One group received an oral dose and the other group
received an intravenous dose. A summary of the some of data obtained from this experiment is given below.
Dose (mg) 8 8 8
AUC
246.5 139 145
AUMC
1138 795 870
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
Anderson, T., et al, "Pharmacokinetics of various single intravenous and oral doses of omeprazole", Eur Journal of Clinical Phar-
macology, 39, (1990), p. 195 - 197.
Omeprazole (mw: 345.42) is an agent which inhibits gastric acid secretion from the parietal cell. It is useful in
treating such problems as ulcers and gastroesophageal reflux disease. One group received an iv bolus dose and the
other group received an oral dose. A summary of the some of data obtained from this experiment is given below.
Dose (mg) 20 40 40
AUC
3.2 3.5 3.0
AUMC
3.2 5.25 4.5
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
mole
L
---------------- hr
,
_
mole
L
---------------- hr
2
,
_
mole
L
----------------
,
_
mole
L
----------------
,
_
mole
L
----------------
,
_
Paroxetine (Problem 8 - 17)
Lund, J., et al., "Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man", Journal
of Pharmacology and Toxicology, Vol. 51, (1982), p. 351 - 357.
Paroxetine kinetics and cardiovascular effects were studied in male subjects after single oral doses of 45 mg
and slow intravenous infusion of 23 - 28 mg. A summary of the some of data obtained from this experiment is given
below.
Dose (mg) 28 45 45
AUC
467 750 675
AUMC
6671 11250 10463
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
Ranitidine (Problem 8 - 18)
Garg, D., et al., "Pharmacokinetics of ranitidine in patients with renal failure", Journal of Clinical Pharmacology, Vol. 26 (1986),
p. 286 - 291.
Ranitidine is an agent used in the treatment of peptic ulceration. In this study, ten patients with renal failure
received either a 50 mg intravenous bolus dose or a 150 mg tablet. A summary of the some of data obtained from this
Dose (mg) 50 150 150
AUC
5159 6422 6753
AUMC
53415 78752 84413
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
Sulpiride (Problem 8 - 19)
Bressolle, F., Bres, J., and Faure-Jeantis, A., "Absolute bioavailability , rate of absorption, and dose proportionality of sulpiride in
humans", Journal of Pharmaceutical Sciences ,Vol. 81, No. 1 (1992), p. 26 - 32.
Sulpiride is a substituted benzamine antipsychotic. In this study, the drug was administered to two groups.
The first group received a 200 mg oral dose and the second group received a 100 mg intravenous infusion. A summary
of the some of data obtained from this experiment is given below.
Dose (mg) 100 200 200 200
AUC
8.27 8.79 8.6 8.0
AUMC
79.1 87.3 91.1 84.5
MRT (hr)
MAT (hr)
ke (hr
-1
)
ka (hr
-1
)
Cp
0

V
d
(L)
Cp at 1 hour
f
Cp
max

T
max
(hr)
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
8.7 Solutions
8.7.1 CAFFEINE ON PAGE 61
Aramaki, S., et al., "Pharmacokinetics of caffeine and its metabolites in horses after intravenous, intramuscular, or oral adminis-
tration", Chem Pharm Bull, Vol. 30, No. 11, (1991), p. 2999 - 3002.
This study deals with the pharmacokinetics of caffeine. Caffeine doses of 2.5 mg/kg were administered both intrave-
nously and orally to horses with an average weight of about 500 kg. A summary of the some of data obtained from this
experiment is given below. Fill in the empty cells.
TABLE 8-25 Caffeine
Dose (mg/kg) 2.5 2.5 2.5 2.5
AUC
63.1 60.7 60 57
AUMC
1442 1556.8 1600 1723
MRT (hr) 22.9 25.7 26.7 30.2
MAT (hr) 2.79 3.81 7.36
ke (hr
-1
)
0.0438
ka (hr
-1
)
0.358 0.262 0.136
Cp
0

2.76
V
d
(L/kg) 0.91
Cp at 1 hour
2.64 0.78 0.59 0.31
f 0.96 0.95 .90
Cp
max

2.76 1.98 1.83 1.45 0.79
T
max
(hr) 6.69 8.19 12.1 1.5
Relative Bioavailability 0.95
Generic Equivalent (Yes / No) NO
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
1. = hours
2. = = 0.044
3. =
4. = 63.1
5. The horses have an average weight of 500 kg.

6.

7.
8.
Where AUMC is that which is given for the oral dose.
Where AUC is that which is given for the oral dose.
9. =
MRT
AUMC
AUC
------------------ =
1442
ug h
2
mL
----------------
63.1
ug h
2
mL
----------------
---------------------------- 22.9 =
k
1
MRT
------------ =
1
22.9h
------------- h
1
t
1 2
2 ln
k
-------- =
0.693
0.044h
1
--------------------- 15.75h =
Cp
0
AUC k =
ug h
mL
------------- 0.0044h
1
2.76
ug
mL
-------- =
Dose 2.5
mg
kg
------- 500kg 1250mg = =
Cp
0
2.78
ug
mL
-------- = 2.78
mg
L
------- =
V
d
Dose
Cp
0
-------------
1250mg
2.78
mg
L
-------
-------------------- 449.6L
2.5mg kg
2.78
mg
L
-------
------------------------- 0.91
L
kg
------ = = = = =
Cp Cp
0
e
kt
2.78
ug
mL
--------
,
_
e
0.044 1 ( )
( ) 2.64
ug
mL
-------- = = =
f
AUC
oral
Dose
oral
---------------------
Dose
iv
AUC
iv
-----------------
60
ug h
mL
-------------
2.5
mg
kg
-------
--------------------
2.5
mg
kg
-------
63.1
ug h
mL
-------------
------------------------ 0.95 = = =
MRT
po
AUMC
AUC
------------------
1556.8
ug h
2
mL
----------------
60.7
ug h
mL
-------------
--------------------------------- 25.7h = = =
MAT
po
MRT
po
MRT
iv
= 25.7h 22.9h 2.79h =
10.
11.
12.
14. Bioequivalent: Yes if all three = Yes:
CB = 0.95 = Yes
= NO
= NO
k
a
1
MAT
------------
1
2.79
---------- 0.358hr
1
= = =
t
p
k
a
k
-----
,
_
ln
k
a
k
----------------
0.358hr
1
0.044h
1
------------------------
,

_
ln
0.358hr
1
0.044hr
1
------------------------------------------------------ 6.7hr = = =
Cp
max
fD
V
------
ka
ka k
-------------- e
ktp
e
kat p
( )
0.96 1250mg
449L
-----------------------------------
0.358hr
1
0.358 0.044 ( ) hr
1
------------------------------------------------- e
0.044 6.7 ( )
e
0.358 6.7 ( )
( ) = =
AUC
generic
( ) Dose
generic
( )
AUC
Brand
( ) Dose
Brand
( )
----------------------------------------------------------------------
CB
57
ug
mL
-------- hr
,
_
,
_
2.5
mg
km
-------
,
_
60
ug
mL
-------- hr
,
_
,
_
2.5
mg
km
-------
,
_
------------------------------------------------------------- 0.95 = =
0.80 CB 1.25 < <
0.80
t
p
generic
t
p
brand
-------------- 1.25 < <
t
p
generic
t
p
brand
--------------
12.1hr
8.19hr
---------------- 1.5 = =
0.80
C
p
max g eneric
C
p
max b rand
------------------------ 1.25 < <
C
p
max g eneric
C
p
max b rand
------------------------
1.45
ug
mL
--------
1.83
ug
mL
--------
------------------- 0.79 = =
8.7.2 CEFETAMET PIVOXIL ON PAGE 62
Ducharme, M., et. al., "Bioavailability of syrup and tablet formulations of cefetamet pivoxil", Antimicrobial Agents and Chemo-
therapy, Vol. 37, No. 12, (1993), p. 2706 - 2709.
Cefetamet pivoxil is a prodrug of cefetamet. This study compares the bioavailability of cefetamet pivoxil in tablet
form versus syrup form. A summary of the some of data obtained from this experiment is given below. Fill in the
approprate cells.
.
1. = hours
Where AUMC is that which is given for the intravenous dose.
Where AUC is that which is given for the intravenous dose.
Dose (mg) 250 500 500 500
AUC
30.64 53.68 50 47
AUMC
101.66 191.64 205.6 225.3
MRT (hr) 3.32 3.57 4.11 4,79
MAT (hr) 0.252 0.794 1.48
ke (hr
-1
)
0.301
ka (hr
-1
)
3.97 1.26 0.678
Cp
0

9.23
V
d
(L) 27.1
Cp at 1 hour
6.83 12.62 9.03 5.91
f 0.88 0.82 0.77
Cp
max

9.23 13.1 9.6 7.4 0.77
T
max
(hr) 0.70 1.49 2.15 1.44
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
MRT
AUMC
AUC
------------------ =
101.66
mg h
2
L
-----------------
30.64
mg h
2
L
-----------------
---------------------------------- 3.32 =
2. = = 0.301
3. =
4. = 30.64
5.
6.
7.
8.
Where AUMC is that which is given for the oral dose.
Where AUC is that which is given for the oral dose.
9. =
10.
11.
12.
k
1
MRT
------------ =
1
3.32h
------------- h
1
t
1 2
2 ln
k
-------- =
0.693
0.301h
1
--------------------- 2.3h =
Cp
0
AUC k =
mg h
L
--------------- 0.301h
1
9.22
mg
L
------- =
V
d
Dose
Cp
0
-------------
250mg
9.24
mg
L
-------
------------------ 27.06L = = =
Cp Cp
0
e
kt
9.24
mg
L
-------
,
_
e
0.301 1 ( )
( ) 6.84
mg
L
------- = = =
f
AUC
oral
Dose
oral
---------------------
Dose
iv
AUC
iv
-----------------
53.68
mg h
L
---------------
500mg
-----------------------------
250mg
30.64
mg h
L
---------------
----------------------------- 0.876 = = =
MRT
po
AUMC
AUC
------------------
191.64
mg h
2
L
-----------------
53.68
mg h
L
---------------
---------------------------------- 3.57h = = =
MAT
po
MRT
po
MRT
iv
= 3.57h 3.32h 0.252hr =
k
a
1
MAT
------------
1
0.252
------------- 3.97hr
1
= = =
t
p
k
a
k
-----
,
_
ln
k
a
k
----------------
4.0h
1
0.301h
1
---------------------
,

_
ln
4.0h
1
0.301h
1
------------------------------------------- 0.7h = = =
Cp
max
fD
V
------
ka
ka k
-------------- e
kt
e
k
a
t
( )
0.88 500mg ( )
27.1L
--------------------------------
3.97hr
1
3.97 0.301 ( ) hr
1
---------------------------------------------- e
0.301 0.7 ( )
e
3.97 0.7 ( )
( ) 13.1
mg
L
------- = = =
AUC
generic
( ) Dose
generic
( )
AUC
Brand
( ) Dose
Brand
( )
----------------------------------------------------------------------
14. Bioequivalent: Yes if all three = Yes:
CB = 0.94 = Yes
= NO
= NO
CB
47
ug
mL
-------- hr
,
_
,
_
500mg
50
ug
mL
-------- hr
,
_
,
_
500mg
-------------------------------------------------------- 0.94 = =
0.80 CB 1.25 < <
0.80
t
p
generic
t
p
brand
-------------- 1.25 < <
t
p
generic
t
p
brand
--------------
2.15hr
1.49hr
---------------- 1.44 = =
0.80
C
p
max g eneric
C
p
max b rand
------------------------ 1.25 < <
C
p
max g eneric
C
p
max b rand
------------------------
7.4
ug
mL
--------
9.6
ug
mL
--------
---------------- 0.77 = =
8.7.3 CEFIXIME ON PAGE 63
Faulkner, R. ,et al., "Absolute bioavailability of cefixime in man", Journal of Clinical Pharmacology, Vol. 28 (1988), p. 700 - 706.
Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram nega-
tive bacteria. In this study, sixteen subjects each received a 200 mg intravenous dose and then a 200 mg capsule with a
washout period between the administration of each dosage form. A summary of the some of data obtained from this
Dose (mg) 200 200 200
AUC
47 23.6 20.2
AUMC
183.3 162.8 187.5
MRT (hr) 3.9 6.9 9.3
MAT (hr) 3.0 5.38
ke (hr
-1
)
0.256
ka (hr
-1
)
0.334 0.186
Cp
0

12.1
V
d
(L) 16.6
Cp at 1 hour
9.3 1.5 0.77
f 0.50 0.43
Cp
max

12.1 2.5 1.6 0.64
T
max
(hr) 3.4 4.6 1.33
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
8.7.4 CEFTIBUTEN ON PAGE 64
"The pharmacokinetics of ceftibuten in humans"
Ceftibuten is a new oral cephalosporin with potent activity against enterobacteriaceae and certain gram posi-
tive organisms. In this study two groups received either a 400 mg oral dosage form of ceftibuten or a 200 mg iv bolus
dose of ceftibuten. A summary of the some of data obtained from this experiment is given below.
Dose (mg) 200 400 400 400
AUC
75.2 65.9 64.2 64
AUMC
211.2 213.4 220 208
MRT (hr) 2.94 3.24 3.43 3.25
MAT (hr) 0.297 0.485 0.309
ke (hr
-1
)
0.390
ka (hr
-1
)
3.37 2.06 3.24
Cp
0

25.6
V
d
(L) 7.8
Cp at 1 hour
18.2 16.9 15.3 16.4
f 0.44 0.42 0.43
Cp
max

25.6 17.3 15.3 16.7 1.09
T
max
(hr) 0.76 1.05 0.78 0.74
Relative Bioavailability 1
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
8.7.5 CIMETIDINE ON PAGE 65
Sandborn, W., et al., "Pharmacokinetics and pharmacodynamics of oral and intravenous cimetidine in seriously ill patients", Jour-
nal of Clinical Pharmacology, Vol. 30, (1990), p. 568 - 571.
Cimetidine is a histamine receptor antagonist which is used in the treatment of gastric and duodenal ulcer dis-
ease. In this study, patients received 300 mg of cimetidine as an iv bolus on the first day and data was collected. On
the second day, the patients received 300 mg orally and data was collected. A summary of the some of data obtained
Dose (mg) 300 300 300
AUC
3.81 2.48 2.50
AUMC
5.33 11.73 10.73
MRT (hr) 1.40 4.73 4.29
MAT (hr) 3.33 2.89
ke (hr
-1
)
0.715
ka (hr
-1
)
0.300 0.346
Cp
0

2.72
V
d
(L) 110
Cp at 1 hour
1.33 0.32 0.37
f 0.65 0.66
Cp
max

2.72 0.40 0.44 1.1
T
max
(hr) 2.1 2.0 0.94
Relative Bioavailability 1
Generic Equivalent (Yes / No) YES
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
8.7.6 DIURNAL VARIABILITY IN THEOPHYLLINE BIOAVAILABILITY
ON PAGE 66
Bauer, L., Gibaldi, M., and Vestal, R., "Influence of pharmacokinetic diurnal variation on bioavailability estimates", Clinical Phar-
macokinetics, vol. 9, (1984), p. 184 - 187.
This article discusses the effects of diurnal variation on the bioavailability and clearance of theophylline. In
this study patients received a 500 mg dose every 12 hours either orally or by iv bolus. A summary of the some of data
obtained from this experiment for the time period between midnight and noon is given below.
Dose (mg) 500 500 500 500
AUC
160.25 144.58 140 144
AUMC
1821 1662 1785 1700
MRT (hr) 11.40 11.50 12.75 11.8
MAT (hr) 0.13 1.39 0.44
ke (hr
-1
)
0.088
ka (hr
-1
)
7.58 0.721 2.26
Cp
0

14.1
V
d
(L) 35.5
Cp at 1 hour
12.9 11.8 6.02 10.7
f 0.90 0.87 0.90
Cp
max

14.1 12.1 9.20 11.1 1.21
T
max
(hr) .059 3.3 1.5 0.45
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
8.7.7 CIS-5-FLUORO-1-[2-HYDROXYMETHYL-1,3-OXATHIOLAN-5-YL]
CYTOSINE (FTC) ON PAGE 67
Frick, L. , et al., "Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-Fluoro-1-[2-Hydroxyme-
thyl-1,3-Oxathiolan-5-yl] Cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus", Anti-
microbial Agents and Chemotherapy, Vol. 37, No. 11, (1993), p. 2285 - 2292.
FTC is a 2',3'-didoexynucleoside analog that may be useful against HIV and HBV. In this study, rats with an
average weight of 270 g were given either iv or oral doses of 100 mg/kg. A summary of the some of data obtained
Dose (mg/kg) 100 100 100
AUC
265 168 175
AUMC
19514 12600 13125
MRT (hr) 73.6 75 75
MAT (hr) 1.36 1.36
ke (hr
-1
)
.0136
ka (hr
-1
)
0.734 0.734
Cp
0

3.6
V
d
(L/kg) 27.7
Cp at 1 hour
3.55 1.18 1.23
f 0.63 0.66
Cp
max

3.6 2.1 2.2 1.04
T
max
(hr) 5.54 5.54 1.0
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
8.7.8 HYDROMORPHONE ON PAGE 68
Vallner, J., et al., "Pharmacokinetics and bioavailability of hydromorphone following intravenous and oral administration to
human subjects", Journal of Clinical Pharmacology, Vol. 21, (1981), p. 152 - 156.
Hydromorphone hydrochloride is an analog of morphine which has about seven times the effect of morphine
when given intravenously. In this study, volunteers were given a 2 mg intravenous dose and a 4 mg oral dose of hydro-
morphone on separate days. A summary of the some of data obtained from this experiment is given below.
Dose (mg) 2 4 4
AUC
83 87.2 96
AUMC
289.4 401 432
MRT (hr) 3.49 4.60 4.50
MAT (hr) 1.11 1.03
ke (hr
-1
)
0.287
ka (hr
-1
)
0.899 0.987
Cp
0

23.8
V
d
(L) 84
Cp at 1 hour
17.9 12.6 14.7
f 0.53 0.56
Cp
max

23.8 14.6 16.6 1.13
T
max
(hr) 1.87 1.77 0.95
ug
L
------ hr
,
_
ug
L
------ hr
2
,
_
ug
L
------
,
_
ug
L
------
,
_
ug
L
------
,
_
8.7.9 ISOSORBIDE DINITRATE ON PAGE 69
Straehl, P. and Galeazzi, R., "Isosorbide dinitrate bioavailability , kinetics, and metabolism", Clinical Pharmacology and Thera-
peutics, Vol. 38m (1985), p. 140 - 149.
Isosorbide dinitrate is used in the treatment of angina pectoris, vasospastic angina, and congestive heart failure.
In this study volunteers received a 5 mg intravenous dose and a 10 mg tablet. The different dosage forms were sepa-
rated by a washout period. A summary of the some of data obtained from this experiment is given below.
Dose (mg/kg) 5 10 10
AUC
370.3 158 165
AUMC
487 310 305
MRT (hr) 1.32 1.96 1.85
MAT (hr) 0.65 0.53
ke (hr
-1
)
0.760
ka (hr
-1
)
1.546 1.875
Cp
0

282
V
d
(L) 17.75
Cp at 1 hour
132 60.1 66.2
f 0.21 0.22
Cp
max

282 60.4 67.8 1.12
T
max
(hr) 0.90 0.81 0.90
ug
L
------ hr
,
_
ug
L
------ hr
2
,
_
ug
L
------
,
_
ug
L
------
,
_
ug
L
------
,
_
8.7.10 KETANSERIN ON PAGE 70
Kurowski, M., "Bioavailability and pharmacokinetics of ketanserin in elderly subjects", Journal of Clinical Pharmacology, Vol. 28,
(1988), p. 700 - 706.
Ketanserin is a 5-hydroxytryptamine S2-antagonist. This study focuses on the kinetics of Ketanserin in the
elderly. Subjects were given either a 10 mg intravenous dose or a 40 mg oral tablet. A summary of the some of data
Dose (mg) 10 40 40
AUC
541 112.5 103.9
AUMC
11700 24900 22900
MRT (hr) 21.6 22.1 22.0
MAT (hr) 0.5 0.4
ke (hr
-1
)
0.0402
ka (hr
-1
)
2.0 2.5
Cp
0

25.0
V
d
(L) 400
Cp at 1 hour
23.9 43.6 42.7
f .052 0.48
Cp
max

25.0 47.6 44.5 0.94
T
max
(hr) 1.93 1.63 0.84
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
8.7.11 METHOTREXATE ON PAGE 71
Seideman, P., et al., " The pharmacokinetics of methotrexate and its 7-hydroxy metabolite in patients with rheumatoid arthritis",
British Journal of Clinical Pharmacology, 35 (1993), p. 409 - 412.
The drug Methotrexate is a folic acid which has been shown to inhibit dihydrofolate reductase. The impor-
tance of this drug at present is mostly seen in the area of oncology, but lately it has been used for rheumatoid arthritis.
Methotrexate has a molecular weight of 454.4. In this study, the drug was administered both by IV bolus and orally as
a 15 mg dose. The following data was obtained:
Dose (mg) 15 15 15
AUC
2752 2708 2700
AUMC
15887 18400 18500
MRT (hr) 5.77 6.79 6.85
MAT (hr) 1.02 1.08
ke (hr
-1
)
0.173
ka (hr
-1
)
0.979 0.927
Cp
0

477
V
d
(L) 69.3
Cp at 1 hour
401 265 256
f 0.98 0.98
Cp
max

477 323 318 0.98
T
max
(hr) 2.15 2.23 1.04
nmole
L
---------------- hr
,
_
nmole
L
---------------- hr
2
,
_
nmole
L
----------------
,
_
nmole
L
----------------
,
_
nmole
L
----------------
,
_
8.7.12 MOCLOBEMIDE ON PAGE 72
Schoerlin, M. et al., "Disposition kinetics of moclobemide, a new MAO-A inhibitor, in subjects with impaired renal function", Jour-
nal of Clinical Pharmacology, Vol. 30 (1991), p. 272 - 284.
Moclobemide is an antidepressant agent that reversibly inhibits the A-isozyme of the monoamine oxidase
enzyme system. In this study, single IV and oral doses were administered to a patient. A summary of the some of data
Dose (mg) 150 100 100
AUC
2.58 1.70 1.52
AUMC
6.35 5.91 5.90
MRT (hr) 2.46 3.48 3.80
MAT (hr) 1.02 1.42
ke (hr
-1
)
0.406
ka (hr
-1
)
0.985 0.704
Cp
0

1.05
V
d
(L) 143
Cp at 1 hour
0.698 0.344 0.250
f .099 .088
Cp
max

1.05 .037 0.29 .079
T
max
(hr) 1.53 1.85 1.21
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
8.7.13 NALBUPHINE ON PAGE 73
Nalbuphine hydrochloride is an agonist-antagonist opiod which is used for its analgesic actions. In this study,
volunteers were given single doses of four different nalbuphine forms. The data below focuses on a 10 mg iv dose and
a 45 mg dose of an oral solution. A summary of the some of data obtained from this experiment is given below.
Dose (mg) 10 45 40 40
AUC
86.9 70.3 62.5 60
AUMC
288 306 280 270
MRT (hr) 3.31 4.35 4.48 4.5
MAT (hr) 1.04 1.17 1.19
ke (hr
-1
)
.0301
ka (hr
-1
)
0.963 0.858 0.843
Cp
0

26.2
V
d
(L) 381
Cp at 1 hour
19.4 11.1 9.2 8.7
f 0.180 0.180 0.173
Cp
max

26.2 12.5 10.7 10.2 0.95
T
max
(hr) 1.76 1.88 1.90 1.01
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
8.7.14 NEFAZODONE ON PAGE 74
Shukla, U. et al., "Pharmacokinetics, absolute bioavailability, and disposition of nefazodone in the dog", Drug Metabolism and
Disposition, Vol. 21, No. 3, (1993), p. 502 - 507.
Nefazodone was given to four healthy, adult, male beagles with an average weight of 11.0 kg. Each dog was
given a 10 mg/kg dose as a either a intravenous injection or as an oral solution or tablet. A summary of the some of
data obtained from this experiment is given below.
Dose (mg/kg) 10 10 10 10
AUC
6023 829 800 700
AUMC
29283 4875 4800 4500
MRT (hr) 4.86 5.88 6.0 6.43
MAT (hr) 1.02 1.14 1.57
ke (hr
-1
)
0.210
ka (hr
-1
)
0.982 0.879 0.638
Cp
0

1238
V
d
(L) 8.07
Cp at 1 hour
1009 94.8 85.7 60.7
f 0.138 0.133 0.116
Cp
max

1238 112.7 105.6 84.0 0.80
T
max
(hr) 2.0 2.16 2.62 1.21
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
8.7.15 ONDANSETRON ON PAGE 75
Colthup, P., et al., "Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly", Journal of Phar-
maceutical Sciences, Vol. 80, No. 9(1991), p. 868 - 871.
Ondansetron is a 5-hydroxyltryptamine compound which is useful in treating the nausea and vomiting which is
caused by the use of chemotherapy and radiation in the cancer patients. In order to determine the absolute bioavailabil-
ity of oral Ondansetron, doses of 8 mg were given to two groups. One group received an oral dose and the other group
received an intravenous dose. A summary of the some of data obtained from this experiment is given below.
Dose (mg) 8 8 8
AUC
246.5 139 145
AUMC
1138 795 870
MRT (hr) 4.62 5.72 6.0
MAT (hr) 1.10 1.38
ke (hr
-1
)
0.217
ka (hr
-1
)
0.907 0.723
Cp
0

53.4
V
d
(L) 150
Cp at 1 hour
43 15.9 14.7
f 0.56 0.59
Cp
max

53.4 19.2 18.8
T
max
(hr) 2.1 2.4 1.1
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
8.7.16 OMEPRAZOLE ON PAGE 76
Anderson, T., et al, "Pharmacokinetics of various single intravenous and oral doses of omeprazole", Eur Journal of Clinical Phar-
macology, 39, (1990), p. 195 - 197.
Omeprazole (mw: 345.42) is an agent which inhibits gastric acid secretion from the parietal cell. It is useful in
treating such problems as ulcers and gastroesophageal reflux disease. One group received an iv bolus dose and the
other group received an oral dose. A summary of the some of data obtained from this experiment is given below.
Dose (mg) 20 40 40
AUC
3.2 3.5 3.0
AUMC
3.2 5.25 4.5
MRT (hr) 1.0 1.5 1.5
MAT (hr) 0.5 0.5
ke (hr
-1
)
1
ka (hr
-1
)
2 2
Cp
0

3.2
V
d
(L) 52.4
Cp at 1 hour
1.18 1.63 1.40
f 0.55 0.47
Cp
max

3.2 1.8 1.5 0.86
T
max
(hr) 0.69 0.69 1
mole
L
---------------- hr
,
_
mole
L
---------------- hr
2
,
_
mole
L
----------------
,
_
mole
L
----------------
,
_
mole
L
----------------
,
_
8.7.17 PAROXETINE ON PAGE 77
Lund, J., et al., "Paroxetine: pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man", Journal
of Pharmacology and Toxicology, Vol. 51, (1982), p. 351 - 357.
Paroxetine kinetics and cardiovascular effects were studied in male subjects after single oral doses of 45 mg
and slow intravenous infusion of 28 mg. A summary of the some of data obtained from this experiment is given below.
Dose (mg) 28 45 45
AUC
467 750 675
AUMC
6671 11250 10463
MRT (hr) 14.3 15 15.5
MAT (hr) 0.72 1.22
ke (hr
-1
)
0.07
ka (hr
-1
)
1.40 .082
Cp
0

32.7
V
d
(L) 856
Cp at 1 hour
30.5 37.9 25.5
f 1 0.90
Cp
max

32.7 44.8 37.6 0.84
T
max
(hr) 2.25 3.27 1.45
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
8.7.18 RANITIDINE ON PAGE 78
Garg, D., et al., "Pharmacokinetics of ranitidine in patients with renal failure", Journal of Clinical Pharmacology, Vol. 26 (1986),
p. 286 - 291.
Ranitidine is an agent used in the treatment of peptic ulceration. In this study, ten patients with renal failure
received either a 50 mg intravenous bolus dose or a 150 mg tablet. A summary of the some of data obtained from this
Dose (mg) 50 150 150
AUC
5159 6422 6753
AUMC
53415 78752 84413
MRT (hr) 10.4 12.3 12.5
MAT (hr) 1.91 2.15
ke (hr
-1
)
0.0966
ka (hr
-1
)
0.524 0.466
Cp
0

498
V
d
(L) 100
Cp at 1 hour
452 240 231
f .0415 0.436
Cp
max

498 423 432 1.02
T
max
(hr) 3.96 4.26 1.07
ng
mL
-------- hr
,
_
ng
mL
-------- hr
2
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
ng
mL
--------
,
_
8.7.19 SULPIRIDE ON PAGE 79
Bressolle, F., Bres, J., and Faure-Jeantis, A., "Absolute bioavailability , rate of absorption, and dose proportionality of sulpiride in
humans", Journal of Pharmaceutical Sciences ,Vol. 81, No. 1 (1992), p. 26 - 32.
Sulpiride is a substituted benzamine antipsychotic. In this study, the drug was administered to two groups.
The first group received a 200 mg oral dose and the second group received a 100 mg intravenous infusion. A summary
of the some of data obtained from this experiment is given below.
Dose (mg) 100 200 200 200
AUC
8.27 8.79 8.6 8.0
AUMC
79.1 87.3 91.1 84.5
MRT (hr) 9.56 9.93 10.6 10.6
MAT (hr) 0.367 1.02 1.0
ke (hr
-1
)
0.865
ka (hr
-1
)
2.72 0.972 1.0
Cp
0

0.865
V
d
(L) 116
Cp at 1 hour
0.779 0.798 0.526 0.498
f 0.53 0.52 0.48
Cp
max

0.865 0.807 0.687 0.643 0.94
T
max
(hr) 1.24 2.57 2.52 0.98
ug
mL
-------- hr
,
_
ug
mL
-------- hr
2
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
ug
mL
--------
,
_
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136. Conlan, M.F., More Charges Coming in Generic Industry Probe, Drug Topics, 135(2):56-57, 1991.
137. Yorke, J., FDA Ensures Equivalence of Generic Drugs, FDA Consumer, Sept:11-15, 1992.
138. Thompson, L.R., After the Scandals: New Generic Counseling, Am. Pharm., NS30(7):31-33, 1990.
139. Conlan, M.F., After the Storm, Drug Topics, 135(12):40-44, 1991.
140. Martin, S., Generic Drug Scandals Raise Questions About Safety, Am. Pharm., NS29(10):23-24, 1989.
141. Spalding, B.J., The Generic Industry: One Year Later, Am. Drug., 202(3):14- 16, 1990.
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144. Consumer Confidence in Generic Drug Products Down in Wake of Industry Scandal, But Satisfaction with
Products Remains High, Survey Reveals, A.J.H.P., 47:468, 1990.
145. Pal, S. and D'Angelo, A.C., FDA Reputation Suffers, Pharmacists Ask for More Product Information, U.S.
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146. Gross, L.H., Can Pharmacists, Physicians, and the Public Trust Generics? Am. Druggist, 200(3):25-28, 1989.
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152. Summers, K.H., Counseling Patients Who Take Generic Drug Products, Drug Topics (Supplement):45S-54S,
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54(10):55-62, 1988.
156. Simonsen, L., Rx Dispensing Trends: Pharmacists Make More Selection Decisions, Pharm. Times,
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157. Simonsen, L., Rx Brand Choice: Pharmacists Decide for 35% of All New Rxs, Pharm. Times, 58(10):92-98,
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1993.
159. D'Angelo, A.C., How To Win Pharmacists and Influence Purchasing, U.S. Pharm., 16(6):35-36, 1991.
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1990.
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1991.
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1989.
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171. Locniskar, A., Greenblatt, D.J., Harmatz, J.S., and Shader, R.I., Bioinequivalence of a Generic Brand of Diaz-
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5(11):718-721, 1990.
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Therapy, 3(1):83-87, 1988.
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CHAPTER 9 Clearance
OBJECTIVES
1. Given patient information regarding organ function, the student will calculate (III)
changes in clearance and other pharmacokinetic parameters inherent in compro-
mised patients.
2. Determine the total clearance based on Dose and AUC.
3. Determine clearance of an organ based on dose, AUC, and fraction of drug elimi-
nated by the organ
4. Determine change in clearance due to functional changes in an organ.
5. Determine change in clearance due to change in blood flow through an organ.
6. Prepare a professional consult (V) and justify (VI) modifications in drug therapy
based on clearance of a drug.
Clearance
9.1 Equations
(EQ 9-1)
(EQ 9-2)
(EQ 9-3)
(EQ 9-4)
(EQ 9-5)
(EQ 9-6)
(EQ 9-7)
(EQ 9-8)
(EQ 9-9)
(EQ 9-10)
(EQ 9-11)
(EQ 9-12)
(EQ 9-13)
(EQ 9-14)
(EQ 9-15)
Cl
Rate of Elimination
Serum Concentration
--------------------------------------------------- =
Cl
tot
f D os
AUC
---------------- =
Cl
r
Cl
tot
Fraction of drug that is renally eliminated ( ) =
Cl
H
Cl
tot
Fraction of drug that is hepatically eliminated ( ) =
Q
r
0.0191
L
min kg
-------------------- renal blood perfusion 70kg 60
min
hr
--------- 80
L
hr
-----blood =
Q
H
0.0238
L
min kg
-------------------- hepatic blood perfusion 70kg 60
min
hr
--------- 100
L
hr
-----blood =
E
r
Cl
r
( ) Q
r
=
E
H
Cl
H
( ) Q
H
=
f
u
Cl
int
Q Cl
Q Cl
---------------- =
Cl
int
Q Cl
Q Cl
----------------
f
u
---------------- =
F
i
f
u
Cl
int
f
u
Cl
int
-------------------------- =
F
R
Q
Q
------- =
F
Cl
F
i
F
R
F
R
E
r
F
i
F
R
( ) +
----------------------------------------- =
F
Cl
t ot
Cl
tot
Cl
tot
--------------
k
k V
----------------
Cl
H
Cl
r
+
Cl
H
Cl
r
+
----------------------------- = = =
0.80 F
Cl
t ot
1.20
Clearance
9.2 Definitions and Terms
Clearance: The hypothetical volume of a fluid from which a substance is
totally and irreversibly removed per unit time.
Dimensions:
Examples of fluids: blood, serum, plasma, bile, gut contents, CSF.
Systemic or Total Body Clearance: Removal process is elimination
(excretion and metabolism). Fluid is usually plasma or serum (rarely blood).
Renal Clearance: Removal process is urinary excretion of
unchanged drug. Fluid is usually plasma or serum (rarely blood).
Metabolic Clearance: Removal process is metabolism. Fluid is usu-
ally blood (rarely plasma or serum).
Hepatic Clearance: This is when the liver is the metabolic
organ.
Creatinine Clearance: This is applied to endogenous creatinine.
It is used to monitor renal function, and thus is a valuable parameter for calculating
dosage regimens in elderly patients or those suffering from renal dysfunction. Cre-
atinine
Value for normal males: 117 20 ml/min
Value for normal females: 108 20 ml/min
Inulin Clearance: This is for inulin, and yields the glomerular
filtration rate.
Value for normal males: 124.5 9.7 ml/min
Value for normal females: 108.8 13.5 ml/min
L
3
T
Cl ( ) , Cl
tot
( )
Cl
r
( )
Cl
m
( )
Cl
H
( ) Cl
m
Cl
cr
( ) Cl
r
t
1 2
231min =
Cl
inulin
Cl
r
Clearance
9.3 Measurement of Creatinine Clearance
The mass of endogenous creatinine excreted into the urine collected over a given
time interval is determined. The mean serum creatinine concentration
over that interval is calculated from sample determinations; this should be the con-
centration halfway through the interval. In practice, and, as is rela-
tively constant, the serum sample is taken at any convenient time.
Let a be a volume of serum having a creatinine concentration of . The mass
of creatinine in the serum will be . If this creatinine is totally and irrevers-
ibly removed from the serum to the urine in the time interval, , then
(EQ 9-16)
Thus, (EQ 9-17)
The volume of serum from which this creatinine is removed in unit time is ;
this is the definition of clearance. Hence,
(EQ 9-18)
Siersbaek-Neilson et al. report a value of 11.1 for in 149 males (aged
20-99). The value of decreased with age from 16.53 per Kg body
weight (age 20-29) to 6.53 per Kg body weight (age 90-99). For a 25 year
old 70Kg male, equation 9-18 yields
t ( ) C
s
( )
cr
t 24hr = C
s
( )
cr
C
s
( )
cr
a C
s
( )
cr
t
a C
s
( )
cr
X
u
=
a
X
u
C
s
( )
cr
--------------- =
a t
Cl
cr
a
t
-----
X
u
t ( )
T
C
s
( )
cr
--------------------------- = =
g ml C
s
( )
cr
X
u
t ( )
T
g min
g min
Cl
cr
104.2
ml
min
--------- =
Clearance
9.4 Model Correlations
Although intrinsically model independent, clearance can also be related to com-
partmental models.
9.4.1 RENAL CLEARANCE
The plasma renal clearance of a drug may be measured analogously to creatinine
clearance:
(EQ 9-19)
The practical versions of and states:
(EQ 9-20)
Comparing equation 9-19 and equation 9-20,
(EQ 9-21)
This relates clearance to model parameters. What is the slope of a plot of
against ?
Note that if (males), it may indicate active secretion of the drug
into the kidney tubules. If (females), it may indicate reabsorp-
tion of the drug from the kidney tubules.
9.4.2 SYSTEMIC CLEARANCE AND METABOLIC CLEARANCE
How could you measure
? and
By analogy,
(EQ 9-22)
and , so .
Consequently, fractional changes in clearance,
Cl
r
X
u
t ( )
T
C
p
--------------------------- =
X
u
t ( )
T
k
u
X k
u
VC
p
= =
Cl
r
k
u
V =
X
u
t ( )
T
C
p
Cl
r
117 20ml min t >
Cl
r
108 20ml min t <
Cl Cl
m
Cl
tot
KV
0.693V
t
1 2
----------------- = =
K k
u
k
m
+ = Cl
tot
Cl
r
Cl
m
+ =
Clearance
(EQ 9-23)
where is new or altered variable. Hepatic function and renal function are not a
priori connected, although some physiological functional changes might result in
similar changes in clearance of both organs. We can see from equation 9-12 that
changes in total body clearance can result in changes in either K, V, or both. The
consequences of that will be discussed in the section on dosage regimens.
9.4.3 USE IN PHARMACOKINETIC EQUATIONS
Systemic Clearance (Cl) can be used in many equations where the drug is removed
by elimination (renal excretion and metabolism). If renal excretion is the only
removal process, use l if metabolism, use . Some examples:
Intravenous infusion:
Oral and Intravenous Bolus:
This equation becomes a means of calculating Cl from plasma data.
Dosage Regimen:
These examples are all model-independent expressions, which are very useful in
calculating dosage regimens. The importance of clearance terms rests on their abil-
ity to account for variations in both and / or V simultaneously, as both these
parameters can change in disease states and with age.
F
Cl
t ot
Cl
h
Cl
r
+
Cl
h
Cl
r
+
-------------------------
K
K V
---------------- = =
X
Cl
r
Cl
m
C
p
( )
ss
Q
Cl
------ =
Cl
f X
a
( )
0
C
p
t d
0
---------------
fD
C
p
t d
0
---------------
fD
AUC
------------ = = =
C
p
( )
ss
fD
Cl
------------- =
t
1 2
Clearance
9.5 Physiological Factors Affecting Clearance
9.5.1 INTRINSIC CLEARANCE
Intuitively, it may be recognized that two factors will affect the clearance of a
drug:
1. The rate at which blood is presented to the eliminating organ.
2. The intrinsic ability of the eliminating organ to clear the drug.
Mathematically, a hyperbolic equation has been derived to illustrate the relative
effect of these factors. (Note: this is one model of clearance. There are several oth-
ers which also illustrate the effect of these factors.)
Liver Drug Metabolism
(EQ 9-24)
Where is the rate of blood flow through the liver (assumed 23.8 ml/min/Kg
body weight in normal adult),
f
u
is the fraction unbound of the drug, and
is the intrinsic hepatic clearance of the drug.
If there were no physiological limits to the rate of blood flow , hence equa-
tion 9-24 becomes
(EQ 9-25)
This equation provides a definition for intrinsic clearance, namely the clearance of
a drug were there to be no physiological limits on the rate of blood flow through
the clearing organ.
Cl
int
( )
Cl
H
Q
H
f
u
Cl
H
( )
int
Q
H
f
u
Cl
H
( )
int
+
------------------------------------------ =
Q
H
Cl
H
( )
int
Q
H
( )
Cl
H
Cl
H
( )
int
=
Clearance
Kidney drug excretion By analogy for excretion of unchanged drug by the kidney:
(EQ 9-26)
Where is the rate of blood flow through the kidney (assumed 19.1 ml/min per
Kg body weight in normal adults), and
is the intrinsic renal clearance of the drug.
Note that the value of (assumed 1.75 ml.min per Kg body weight in normal
adults) is about 9% of .
9.5.2 EXTRACTION RATIO (E)
This is defined as the ratio of the clearance of a drug compared to the rate of
blood flow through the clearing organ. As such, it indicates what fraction of the
drug in the blood is cleared (extracted) on each passage through the clearing organ.
Note: when using clearance to calculate extraction ratio, blood flow must be used.
Drug metabolism by the
liver
(EQ 9-27)
Where is the steady-state hepatic extraction ratio.
By comparison with equation 9-24,
(EQ 9-28)
Thus, the range of values of is from zero, when , to one, when
or . For example, propanolol has , yielding
and in normal adult males.
Cl
r
Q
r
f
u
Cl
r
( )
int

Q
r
f
u
Cl
r
( )
int
+
--------------------------------------- =
Q
r
Cl
r
( )
int
Cl
cr
Q
r
E
H
Cl
H
Q
H
--------- =
E
H
E
H
f
u
Cl
H
( )
int
Q
H
f
u
Cl
H
( )
int
+
------------------------------------------ =
E
H
Cl
H
( )
int
0 =
Q
H
0 = Cl
H
( )
int
Q
H
E
H
0.75 =
Cl
H
17.9ml
min Kg body weight
----------------------------------------------------- = Cl
H
( )
i nt
71.4ml
min Kg body weight
----------------------------------------------------- =
Clearance
Kidney excretion of
unchanged drug
(EQ 9-29)
(EQ 9-30)
where is the steady-state renal extraction ratio.
Thus the range of values is from zero, when , to one, when or
. For example, digoxin has , yielding
and in normal adult males. In this case, note that
E
r
Cl
r
Q
r
-------- =
E
r
f
u
Cl
r
( )
int
Q
r
f
u
Cl
r
( )
int
+
--------------------------------------- =
E
r
Cl
r
( )
int
0 = Q
r
0 =
Cl
r
( )
int
Q
r
E
r
0.09 = Cl
r
1.72ml
min Kg body weight
----------------------------------------------------- =
Cl
r
( )
int
1.89ml
min Kg body weight
----------------------------------------------------- =
Cl
r
Cl
cr
Clearance
9.6 Hepatic Function and Clearance
9.6.1 ALTERATIONS IN HEPATIC BLOOD FLOW
For a given drug, equation 9-24 predicts that alterations in the hepatic blood perfu-
sion rate will cause a change in drug clearance, assuming the intrinsic hepatic
clearance is unaltered. A general equation may be derived relating the ratio of
hepatic clearances at two blood perfusion rates to the fractional change in perfu-
sion rate and the extraction ratio of the drug.
(EQ 9-31)
where denotes normal hepatic clearance,
denotes altered hepatic clearance
is the new flow rate over the old flow rate, the fractional change in blood
perfusion rate, and
is the hepatic extraction ratio under normal conditions.
The equation predicts that, for any given decrease in blood perfusion rate, drugs
having a large normal extraction ratio will experience a proportionally greater
reduction in clearance than drugs having a small normal extraction ratio.
Liver blood flow can be reduced by congestive heart failure, for example. The
intrinsic hepatic clearance can be represented by the inherent activity of the
enzymes responsible for drug metabolism.
9.6.2 ALTERATIONS IN HEPATIC INTRINSIC CLEARANCE
For any given drug, equation 9-24 predicts that alterations in the intrinsic hepatic
clearance will cause a change in drug clearance, assuming the blood flow rate is
unchanged. A general equation may be derived relating the ratio of hepatic clear-
ance at two intrinsic hepatic clearances to the fractional change in intrinsic hepatic
and the extraction ratio of the drug.
Cl
H
Cl
H
------------
F
R
F
R
E
H
1 F
R
( ) +
----------------------------------------- =
Cl
H
Cl
H
F
R
Q
H
Q
H
---------- =
E
H
Clearance
(EQ 9-32)
where is the fractional change in fraction unbound times the frac-
tional change in intrinsic hepatic clearance.
The equation predicts that, for any given decrease in intrinsic hepatic clearance,
drugs having a small normal extraction ratio will experience a proportionately
greater reduction in clearance than drugs having a large normal extraction ratio.
The intrinsic hepatic clearance of a drug can be reduced by cirrhosis or increased
by enzyme inducers, such as phenobarbitol.
9.6.3 TABULATED OR GRAPHICAL ALTERATIONS
A table or graph of clearance changes when the hepatic blood flow (but not the
intrinsic hepatic clearance) is altered shows that drugs having a low extraction
ratio need little adjustment in dosage. Even if the hepatic blood flow
were halved , the hepatic clearance is still 91% of its normal value. Con-
versely, dosage adjustment is necessary for drugs having a high extraction ratio
and predominantly eliminated by hepatic metabolism (e.g., propanolol).
A table or graph of clearance changes when the intrinsic hepatic clearance (but not
the hepatic blood flow) is altered shows that drugs having a high extraction ratio
need little adjustment in dosage. Even if the intrinsic hepatic clearance
were halved , the hepatic clearance is still 91% of its normal value. Con-
versely, dosage adjustment is necessary for drugs having a low extraction ratio and
predominately eliminated by hepatic metabolism (e.g., phenylbutazone).
Cl
H
Cl
H
------------
F
i
1 E
H
F
i
1 ( ) +
----------------------------------- =
F
i
f
u
Cl
i nt
( )
f
u
Cl
i nt
( )
------------------------------- =
E
H
0.1 = ( )
F
R
0.5 = ( )
E
H
0.9 = ( )
F
i
0.5 = ( )
Clearance
9.7 Renal Function and Clearance
Approximately 25% of cardiac output goes to the kidneys or approximately 735
ml/min of plasma is presented to the kidneys of a 70 kg man (19.1 mL/min/kg x 70
kg). Approximately 125 ml/min (1.8 mL/min/kg) of that goes to the glomeruli for
filtration (Glomerular Filtration Rate, GFR). Unbound drug is filtered into the
proximal renal tubule at this point. The remaining plasma (as blood) is shunted
around the tubule in the arterioles adjascent to the proximal tubule where drug
may be actively secreted from the arteriol into the proximal tubule or actively
reabsorbed in the opposite direction. As the blood flows down the vessels adjas-
cent to the loop of Henle, the drug may be also passively reabsorbed into the blood
vessel as the water in the urine is being reabsorbed and the urine is being concen-
trated.
This leads to some interesting possibilities:
1. . It is likely that the drug is filtered only, in this case, . It is also possible that
secretion and reabsortion balance and cancel each orther out but are still occurring. The actual
clearance of the drug may be low as the drug may be bound to plasma protiens or red blood
cells.
11. . Net active secretion is infered in this case. These active mechanisms are non-
specific and consequently, drugs actively secreted compete with each other. Secretion, if it
occurs, occurs on the unbound drug and thus is also effected by changes in free fraction. In
cases where secretion is very rapid and as a consequence, virtually all of the drug is removed by
the single pass through the kidney (E
r
~1), the disssociation of the drug from the protien or out
of the red blood cells is not a hinderance. Some reabsorption may occur but it is less than secre-
tion.
12. . Net active reabsorbtion is infered in this case. Active reabsorption occurs for
many exogenous compounds, including glucose and vitamins. For many compounds, reabsorp-
tion is passive, occurring only as a consequence of the concentration gradient produced as water
is removed from the urine as is proceeds down the renal tubule. Since the membrane is lipoidal
in nature, polar compounds, ionized acids and ionized bases are less likely to be reabsorbed.
Thus changing the pH of the urine would result in changing the reabsorption characteristics of
weakly acidic or basic drugs.
For low molecular weight drugs (<2,000 dalton) , filtration always occurs. Active
secretion, active reabsorption and passive reabsorption may occur.
It has been found that renal blood flow is little affected by changes in blood flow
elsewhere. However, in chronic renal dysfunction there are two effects which
exhibit a parallel decline. One is a decrease in glomerular filtration rate (GFR), as
measured by , and the other is the net secretion of drugs into the kidney
tubules. Note that p-amino hippurate (PAH) clearance measures the sum of both
effects.
Cl
r
f
u
GFR =
Cl
r
f
u
GFR >
Cl
r
f
u
GFR <
Cl
cr
Clearance
For any given drug, equation 9-26 predicts that alterations in both the renal blood
perfusion rate (as manifest by the GFR) and the intrinsic renal clearance will cause
a change in drug clearance. A general equation may be derived relating the ratio of
renal clearances at two different blood flow rates and two different intrinsic renal
clearances.
(EQ 9-33)
where is the fractional change in drug unbound times the fractional change in
intrinsic renal clearance.
In this case,
(EQ 9-34)
where is the fractional change in blood flow rate (or GFR).
Thus, equation 9-33 shows that the renal clearance of a drug is reduced by a con-
stant fraction, independent of the renal extraction ratio . This fractional
decrease can be estimated by changes in creatinine clearance:
(EQ 9-35)
where is the altered creatinine clearance
Substituting, equation 9-33 through equation 9-35, we get:
(EQ 9-36)
This equation shows why, in cases of chronic renal dysfunction, a change in the
measured creatinine clearance indicated a likely change in drug renal clearance.
Hence, dosage adjustments are made on this basis, particularly for drugs predomi-
nantly eliminated by renal filtration (e.g., gentamicin, digoxin).
Cl
r
Cl
r
----------- F
i
=
F
i
F
i
f
u
f
u
------- F
R
=
F
R
E
r
( )
F
R
Cl
cr
Cl
cr
------------- =
Cl
cr
Cl
r
Cl
r
-----------
Cl
cr
Cl
cr
------------- =
Clearance
9.8 General Equations for Changes in Clearance
For each clearing organ,
(EQ 9-37)
When a drug has a high extraction ratio, , then equation 9-26 becomes
(EQ 9-38)
and when a drug has a low extraction ratio, , then equation 9-26 becomes
(EQ 9-39)
Thus, the clearance of drugs with a high extraction ratio are more effected by phys-
iological changes in flow of blood to the clearing organ, while drugs with a low
extraction ratio are more effected by physiological changes in the function of the
organ.
9.8.1 PLASMA/BLOOD RATIO
Calculation of Extraction Ratio requires measurement in whole blood by defini-
tion. Since most clinical measurements are done in plasma, knowledge of the
plasma/blood ratio is necessary. Blood in made up of plasma and red blood cells
(RBCs). Thus the amount of drug in the blood is made up of the amount of drug in
the plasma and the amount of drug in the RBCs.
(EQ 9-40)
where
and b = blood, p = plasma, rbc = red blood cell
If we define the ratio of the concentration of the drug in the RBCs to the concentra-
tion of the free drug in plasma as
(EQ 9-41)
and
(EQ 9-42)
F
Cl
Cl
Cl
------
F
I
F
R
F
R
E + F
I
F
R
( )
---------------------------------------- = =
E 1
F
Cl
F
R
E 0
F
Cl
F
I
C
b
V
b
C
p
V
p
C
rbc
V
rbc
+ =
C
x
V
x
AMOUNT
x
=
C
rbc
f
u
C
p
--------------- =
V
rbc
H V
b
=
Clearance
(EQ 9-43)
Pluging equation 9-41 thru equation 9-43 into equation 9-40 results in:
(EQ 9-44)
Rearranging and simplifying results in:
(EQ 9-45)
(EQ 9-46)
Thus equation 9-46 determines the affinity of the drug for the RBCs. Drugs with a
high affinity for the RBCs should result in a smaller volume of distribution.
For drugs that are primarily filtered by the glomeruli, the renal extraction ratio is:
(EQ 9-47)
Putting equation 9-45 into equation 9-47 results in:
(EQ 9-48)
Thus:
1. If the the ratio of to calculated E
rf
from equation 9-48 is one, it is likely that the drug is
filtered only.
rf
from equation 9-48 is greater than one, active secretion
is infered in this case.
rf
from equation 9-48 is less than one, active reabsorb-
tion is infered in this case.
V
p
1 H ( ) V
b
=
C
b
V
b
1 H ( ) V
b
C
p
f
u
H V
b
C
p
+ =
C
b
C
p
------ 1 H f
u
1 ( ) + =
H 1 C
b
C
p
( ) +
f
u
H
----------------------------------------- =
E
rf
Rate of filtration
Rate of presentation
------------------------------------------------
GFR f
u
C
p

Q
r
C
b
-------------------------------- = =
E
rf
GFR f
u
Q
r
1 H f
u
1 ( ) + ( )
----------------------------------------------------------- =
Cl
r
Q
r
--------
Cl
r
Q
r
--------
Cl
r
Q
r
--------
Clearance
9.8.2 HALF LIFE AND ELIMINATION RATE CONSTANT IN RELATIONSHIP
TO CLEARANCE
The elimination rate constant is related to the volume of distribution and the total
body clearance by equation 9-22 above which when rewritten yields:
(EQ 9-49)
(EQ 9-50)
where b = blood and pw
u
= unbound plasma water. Clearance of drug from blood
(Cl
b
) is useful in considering drug extraction in the eliminating organs. Volume
and clearance terms based on unbound drug concentration are particularly useful
in therapeutics, because only the unbound drug is thought to cause the therapeutic
action.
9.8.3 EFFECTS OF ALTERATIONS IN PROTEIN BINDING ON CLEARANCE
Protein binding of drugs may be altered in disease states and by interferance bind-
ing by other drugs on the protein. These changes in binding effect F
i
, the frac-
tional change in intrinsic clearance in both renal and hepatic clearances even
though the actual intrinsic clearance, the indicator of organ function, may be unef-
fected as shown in equation 9-11:

where . Thus, a change in protein binding will cause a proportional
change in F
i
of both clearances. There is more discussion in the chapter on protein
binding.
K
Rate of Elimination
Amount in the body
------------------------------------------------
Mass ( ) Time ( )
Mass
----------------------------------------
Cl
V
------
Volume ( ) Time ( )
Volume
---------------------------------------------- = = = =
K
Cl
V
------
Cl
b
V
b
--------
Cl
pw
u
V
pw
u
------------- = = =
F
i
f
u
Cl
int
f
u
Cl
int
-------------------------- =
Cl
i nt
Cl
int
=
Clearance
9.9 Problems
For each of the problems, do questions A through R now and S through W after
completing chapter 10. In doing questions S through W, please try to obtain a
plasma concentration of free drug within 120 % of normal and 80 % of
.
Cp
ss
max
free
Cp
ss
min
free
Clearance
Acebutolol (Problem 9 - 1)
Piquette-Miller, M., et. al., Effect of aging on the pharmacokinetics of acebutolol enantiomers, Journal of Clinical Pharmacol-
ogy, Vol. 32, (1992), p. 148 - 156. Kukes, VG; Gneushev ET; Mamedov TS; Gneusheva IA; Acebutolol and diacetolol: thier bind-
ing to plasma and erythrocytes and secretion with saliva. Farmakol-Toksikol. 1991 Jan-Feb; 54(1)
Acebutolol is a beta-adrenergic blocking agent which is often used in the treatment of hypertension.(Use Qr = 72 L/hr;
Qh = 90 L/hr)
PROBLEM TABLE 9 - 1. Acebutolol
Patient Condition Normal Normal FRR=0.5 FIR=0.5 FRH=0.5 FIH=0.5
A Dose(mg) 200 400
B f 0.4
C f
u
0.867
D 1.93
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 5.5
H %Cl
r
40
I %Cl
nr
60
J AUC (mg/L*hr) 3.97
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
12
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 1. Answers for Acebutolol
A Dose(mg) 200 400 BID 400 BID 400 BID 400 BID 200 QID
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 1
FRH 1 1 1 1 0.5 1
FIH 1 1 1 1 1 0.5
B f 0.4
C f
u
0.867
D 1.93
E V
d
(L) 160
F
k (hr
-1
)
0.126 0.101 0.102 0.12 0.091
G T
1/2
(hr) 5.5 6.87 6.77 5.89 7.64
H %Cl
r
40 25 26.1 42.9 55.5
I %Cl
nr
60 75 73.9 57.1 44.6
J AUC (mg/L*hr) 3.97 9.93 9.78 8.51 5.5
K (L/hr)
20.2 16.1 16.4 18.8 14.5
L
(L/hr)
12.1 12.1 12.1 10.7 6.5
M
(L/hr)
8.1 4.03 4.27 8.1 8.1
L 0.126
O 0.112
P
(L/hr)
16
Q
(L/hr)
10.5
R F
CL
1 0.8 0.81 0.93 0.72
S
(hr)
12 12 12 12 6
T N 2.18 1.75 1.77 2.04 0.785
U

1.11 1.24 1.23 1.15 1.03
V 0.57 0.72 0.71 0.61 0.80
W 0.25 0.37 0.36 0.28 0.6
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Bisoprolol (Problem 9 - 2)
Kirch, W., et. al., Pharmacokinetics of bisoprolol during repeated oral administration to healthy volunteers and patients with kid-
ney or liver disease, Clinical Pharmacokinetics, Vol. 13, (1987), p. 110 - 117.
Bisoprolol (comes as 5 and 10 mg tablets) is a - selective adrenergic antagonist. It is used in the treatment of hyperten-
sion and angina pectoris.(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 2. Bisoprolol
A Dose(mg) 10 10 TID
B f 0.7
C f
u
1
D 1
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 10
H %Cl
r
50
I %Cl
nr
50
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 2. Answers for Bisoprolol
A Dose(mg) 10 10 10 10 10 10
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 1
FRH 1 1 1 1 0.5 1
FIH 1 1 1 1 1 0.5
B f 0.9
C f
u
0.7
D
E V
d
(L) 152.8
F
k (hr
-1
)
0.0693 0.052 0.0526 0.067 0.0525
G T
1/2
(hr) 10 13.3 13.2 10.3 13.2
H %Cl
r
50 33.3 34 51.3 66
I %Cl
nr
50 66.7 66 48.7 34
J AUC (mg/L*hr) 0.661 0.85 0.87 0.69 0.87
K (L/hr)
10.6 7.94 8.0 10.3 8.0
L
(L/hr)
5.3 5.3 5.3 5.0 2.7
M
(L/hr)
5.3 2.65 2.8 5.3 5.3
L 0.055
O 0.074
P
(L/hr)
5.6
Q
(L/hr)
5.7
R F
CL
1 0.75 0.76 0.97 0.76
S
(hr)
8 12 12 8 12
T N 0.8 0.9 0.9 0.78 0.91
U

0.108 0.099 0.098 0.11 0.098
V 0.083 0.073 0.073 0.085 0.073
W 0.062 0.052 0.052 0.064 0.052
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Cefonicid (Problem 9 - 3)
Fillastre, J., et. al., Pharmacokinetics of cefonicid in uraemic patients, Journal of Antimicrobial Chemotherapy, Vol. 18, (1986),
p. 203 - 211.
Cefonicid is a beta-lactamase resistant cephalosporin which is useful in treating many infections caused by Gram-posi-
tive and Gram-negative organisms. Cefonicid is 80% renally excreted.(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 3. Cefonicid
B f 1
C f
u
0.06
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 5.3
H %Cl
r
80
I %Cl
nr
20
J AUC (mg/L*hr) 654
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 3. Answers for Cefonicid
A Dose(mg) 1000 1000 1000 1000 1000 1000
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 1
FRH 1 1 1 1 0.5 1
FIH 1 1 1 1 1 0.5
B f 1
C f
u
0.06
D
E V
d
(L) 11.7
F
k (hr
-1
)
0.131 0.078 0.079 0.131 0.118
G T
1/2
(hr) 5.3 8.8 8.8 5.3 5.9
H %Cl
r
80 66.7 66.9 80 88.9
I %Cl
nr
20 33.3 33.1 20 11.1
J AUC (mg/L*hr) 654 1090 1083 654 727
K (L/hr)
1.53 0.917 0.93 1.5 1.4
L
(L/hr)
0.3 0.31 0.31 0.3 0.15
M
(L/hr)
1.22 0.612 0.62 1.22 1.22
L 0.0032
O 0.017
P
(L/hr)
5.11
Q
(L/hr)
20.7
R F
CL
1 0.6 0.6 1 0.9
S
(hr)
8 12 12 8 8
T N 1.51 1.4 1.4 1.51 1.36
U

7.9 8.4 8.4 7.9 8.4
V 4.9 5.5 5.4 4.9 5.4
W 2.8 3.3 3.3 2.8 3.3
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Cefpirome (Problem 9 - 4)
Lameire, N., et. al., Single-dose pharmacokinetics of cefpirome in patients with renal impairment, Clinical Pharmacology and
Therapeutics, Vol. 52, (1992), p. 24 - 30.
Cefpirome is a third-generation, broad-spectrum cephalosporin which is useful against many cephalosporin-resistant
organisms.
PROBLEM TABLE 9 - 4. Cefpirome
A Dose(mg) 2000 IV 2000 TID
B f 1
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 2.6
H %Cl
r
85
I %Cl
nr
15
J AUC (mg/L*hr) 342
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 4. Answers for Cefpirome
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Cefprozil (Problem 9 - 5)
Shyu, W., et. al., Pharmacokinetics of cefprozil in healthy subjects and patients with renal impairment, Journal of Clinical Phar-
macology, Vol. 31, (1991), p. 362 - 371.
Cefprozil is a broad-spectrum oral cephalosporin.
PROBLEM TABLE 9 - 5. Cefprozil
A Dose(mg) 1000
B f 0.95
C f
u
0.7
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 1.2
H %Cl
r
75
I %Cl
nr
25
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 5. Answers for Cefprozil
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Chloramphenicol (Problem 9 - 6)
Ambrose, P., Clinical pharmacokinetics of chloramphenicol and chloramphenicol succinate, Clinical Pharmacokinetics, Vol. 9,
(1984), p. 222 - 238.
Chloramphenicol succinate is a prodrug which is converted in vivo to the active form, chloramphenicol.
PROBLEM TABLE 9 - 6. Chloramphenicol
A Dose(mg) 1000
B f 1
C f
u
0.4
D
E V
d
(L/kg) 2.8
F
k (hr
-1
)
G T
1/2
(hr) 0.6
H %Cl
r
30
I %Cl
nr
70
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 6. Answers for Chloramphenicol
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Enalapril (Problem 9 - 7)
Ohnishi, A., et. al., Kinetics and dynamics of enalapril in patients with liver cirrhosis, Clinical Pharmacology and Therapeutics,
Vol. 45, (1989), p. 657 - 665.
Enalapril is an ACE inhibitor which is a prodrug that is metabolized in the liver to the active metabolite, enalaprilat.
PROBLEM TABLE 9 - 7. Enalapril
A Dose(mg) 10 mg po 10 BID1
B f 0.65
C f
u
0.55
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 0.63
H %Cl
r
27
I %Cl
nr
73
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 7. Answers for Enalapril
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Enoxacin (Problem 9 - 8)
Somogyi, A., and Bochner, F., The absorption and disposition of enoxacin in healthy subjects, Journal of Clinical Pharmacol-
ogy, Vol. 28, (1988), p. 707 - 713.
Enoxacin is a fluorinated quinolone which is used to treat infections caused by gram-negative organisms and
Pseudomonoas aeruginosa.
PROBLEM TABLE 9 - 8. Enoxacin
A Dose(mg) 400 200 bid
B f 0.9
C f
u
0.8
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 7.75
H %Cl
r
60
I %Cl
nr
40
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
12
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 8. Answers for Enoxacin
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Enprofylline (Problem 9 - 9)
Nadai, M., et. al, Dose-dependent pharmacokinetics of enprofylline and its renal handling in rats, Journal of Pharmaceutical
Sciences, Vol. 80, No. 7, (1991), p. 648 - 651
Enprogylline is a xanthine bronchodilator which is more potent than theophylline.
PROBLEM TABLE 9 - 9. Enprofylline
TABLE 9 - 9. Answers for Enprofylline
A Dose(mg/kg) 2.5 2.5 TID
B f 1
C f
u
0.4
D
E V
d
(L/kg)
F
k (hr
-1
)
G T
1/2
(hr) 0.36
H %Cl
r
90
I %Cl
nr
10
J AUC (mg/L*hr) 3.6
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Erythromycin (Problem 9 - 10)
Welling and Creig (JPS 67, 1057-9,1978).
Erythromycin is a macrolide antibiotic.(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 10. Erythromycin
B f .8
C f
u
0.06 0.06 0.12 0.06 0.18
D
E V
d
(L) 57 57 100 57 150
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
10
I %Cl
nr
90
J AUC (mg/L*hr)
K (L/hr)
16.5
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
8
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 10. Answers for Erythromycin
A Dose(mg) 300 300 300 200 300 200
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 3
FRH 1 1 1 1 0.5 1
FIH 1 1 1 2 1 0.5
B f .8
C f
u
0.06 0.06 0.12 0.06 0.18
D
E V
d
(L) 57 57 100 57 150
F
k (hr
-1
)
0.255 0.242 0.235 0.227 0.075
G T
1/2
(hr) 2.71 2.85 2.92 3.05 9.27
H %Cl
r
10 5.3 3.1 11.2 37
I %Cl
nr
90 94.7 96.9 88.8 63
J AUC (mg/L*hr) 14.5 17.4 6.7 18.5 14.2
K (L/hr)
16.5 13.8 23.7 13.0 11
L
(L/hr)
13.1 13.1 23.4 11.5 7.02
M
(L/hr)
1.45 0.73 0.73 1.45 4.19
L 0.136
O 0.020
P
(L/hr)
252
Q
(L/hr)
24.7
R F
CL
1 0.95 1.63 0.89 0.77
S
(hr)
8 8 8 8 24
T N 2.94 2.79 2.74 2.63 2.59
U

0.29 0.30 0.23 0.30 0.23
V 0.12 0.13 0.10 0.14 0.11
W 0.038 0.042 0.034 0.049 0.038
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Fleroxacin (Problem 9 - 11)
Singlas, E., et. al., Disposition of fleroxacind, a new trifluoroquinolone, and its metabolites - pharmacokinetics in renal failure
and influence of haemodialysis, Clinical Pharmacokinetics, Vol. 19, No. 1, (1990), p. 67 - 79.
Fleroxacin is a trifluorinated quinolone with activity against a variety of gram-negative and gram-positive organisms.
PROBLEM TABLE 9 - 11. Fleroxacin
A Dose(mg) 400 200 tid
B f 0.95
C f
u
0.5
D 1.45
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 14
H %Cl
r
65
I %Cl
nr
35
J AUC (mg/L*hr) 92
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 11. Answers for Fleroxacin
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Fosinopril (Problem 9 - 12)
Hui, K., et. al., Pharmacokinetics of fosinopril in patients with various degrees of renal function, Journal of Clinical Pharmacol-
ogy and Therapeutics, Vol. 49, No. 4, (1991), p. 457 - 466.
Fosinopril is an angiotensin converting enzyme inhibitor which is a prodrug that is metabolized to active form, fosino-
prilat.
PROBLEM TABLE 9 - 12. Fosinopril
A Dose(mg) 7.5 IV 20 po qd
B f 1 (Oral
0.36)
C f
u
0.01
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 7
H %Cl
r
0
I %Cl
nr
100
J AUC (mg/L*hr) 5.1
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
24
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 12. Answers for Fosinopril

A Dose(mg)
B f
C f
u
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Glutathione (Problem 9 - 13)
Mulders, T., et. al., Characterization of glutathione conjugation in humans: stereoselectivity in plasma elimination pharmacoki-
netics and urinary excretion of (R)- and (S)-2-bromoisovalerylurea in healthy volunteers, Clinical Pharmacology and Therapeu-
tics, Vol. 53, (1993), p. 49 - 58.
This study explored the pharmacokinetics of glutathione.
PROBLEM TABLE 9 - 13. Glutathione
B f 1
C f
u
1
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 4.4
H %Cl
r
35
I %Cl
nr
65
J AUC (mg/L*hr) 276
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 13. Answers for Glutathione

A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Guanadrel (Problem 9 - 14)
Halstenson, C., et. al., Disposition of guanadrel in subjects with normal and impaired renal function, Journal of Clinical Phar-
macology, Vol. 29, (1989), p. 128 - 132.
Guanadrel is adrenergic blocker used in the treatment of hypertension.
PROBLEM TABLE 9 - 14. Guanadrel
A Dose(mg) 25 mg po 25 BID
B f 1
C f
u
0.8
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 3.7
H %Cl
r
40
I %Cl
nr
60
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
12
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 14. Answers for Guanadrel
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Monoxidine (Problem 9 - 15)
Kirch, W., Hutt, H., and Plnitz, V., The influence of renal function on clinical pharmacokinetics of monoxidine, Clinical Phar-
macokinetics, Vol. 15, (1988), p. 245 - 253.
Monoxidine is a centrally acting antihypertensive agent which stimulates -adrenergic receptors.
PROBLEM TABLE 9 - 15. Monoxidine
2
A Dose(mg) 0.25 IV 0.25 tid
B f 1
C f
u
1
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 2.75
H %Cl
r
95
I %Cl
nr
5
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 15. Answers for Monoxidine

A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Nalmefene (Problem 9 - 16)
Dixon, R., et. al., Nalmefence: safety and kinetics after single and multiple oral doses of a new opiod antagonist, Journal of
Clinical Pharmacology, Vol. 27, (1987), p. 233 - 239.
Nalmefene is a pure opiod antagonist which is currently being investigated for use.
PROBLEM TABLE 9 - 16. Nalmefene
A Dose(mg) 20 IV
B f 0.6 oral
C f
u
1
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 9.8
H %Cl
r
70
I %Cl
nr
30
J AUC (mg/L*hr) 0.3
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 16. Answers for Nalmefene

A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Nitrendipine (Problem 9 - 17)
Dylewicz, P, et. al, Bioavailability and elimination of nitrendipine in liver disease, European Journal of Clinical Pharmacology,
Vol, 32, (1987), p. 563 - 568.
Nitrendipine is a calcium antagonist
PROBLEM TABLE 9 - 17. Nitrendipine
A Dose(mg) 5 IV 25 po BID
B f 1 (oral 0.2)
C f
u
0.05
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 11.7
H %Cl
r
0.1
I %Cl
nr
99.9
J AUC (mg/L*hr)
K (L/hr)
90
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 17. Answers for Nitrendipine
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Ofloxacin (Problem 9 - 18)
Lamerire, N., et. al., Ofloxacin pharmacokinetics in chronic renal failure and dialysis, Clinical Pharmacokinetics, Vol. 21, No.
4, (1995), p. 357 - 371.
PROBLEM TABLE 9 - 18. Ofloxacin
A Dose(mg) 300 300
B f 0.93
C f
u
0.74
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 6
H %Cl
r
97
I %Cl
nr
3
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
12
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 18. Answers for Ofloxacin
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 19. Omeprazole
TABLE 9 - 19. Answers for Omeprazole
A Dose(mg) 10 10 BID
B f 0.5 0.75
C f
u
0.04 0.06 0.08
D
E V
d
(L) 30
F
k (hr
-1
)
G T
1/2
(hr) 2
H %Cl
r
0
I %Cl
nr
100
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
12
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
A Dose(mg) 10 10 10 5 10 5
Clearance
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 2
FRH 1 1 1 1 0.5 1
FIH 1 1 1 1.5 1 0.5
B f 0.5 0.75
C f
u
0.04 0.06 0.08
D
E V
d
(L) 30
F
k (hr
-1
)
0.347 0.347 0.493 0.31 0.184
G T
1/2
(hr) 2 2 1.41 2.2 3.8
H %Cl
r
0
I %Cl
nr
100
J AUC (mg/L*hr) 0.48 0.48 0.338 0.53 0.68
K (L/hr)
10.4 10.4 14.8 9.38 5.5
L
(L/hr)
10.4 10.4 14.8 9.38 5.5
M
(L/hr)
0 0 0 0 0
L 0.108
O 0
P
(L/hr)
291.5
Q
(L/hr)
0
R F
CL
1 1 1.42 0.90 0.53
S
(hr)
6 6 8 6 12
T N 3 3 2.83 2.71 3.2
U

0.0076 0.0076 0.0051 0.0079 0.011
V 0.0032 0.0032 0.0025 0.0035 0.0045
W 0.00095 0.00095 0.00099 0.0012 0.0012
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Piperacillin (Problem 9 - 20)
Johnson, C., et. al., Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal disease, Clinical Phar-
macology and Therapeutics, Vol. 51, (1992), p. 32 - 41.
Piperacillin is a beta-lactam antibiotic.
PROBLEM TABLE 9 - 20. Piperacillin
A Dose(mg) 3000 2000 qid
B f 1
C f
u
0.82
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 0.95
H %Cl
r
75
I %Cl
nr
25
J AUC (mg/L*hr) 276
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
6
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 20. Answers for Piperacillin
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Piroxicam (Problem 9 - 21)
Boudinot, S., Funderburg, E., and Boudinot, F., Effects of age on the pharmacokinetics of piroxicam in rats, Journal of Pharma-
ceutical Sciences, Vol. 82, No. 3, (1993), p. 254 - 257.
Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) commonly used in the treatment of arthritis.
PROBLEM TABLE 9 - 21. Piroxicam
A Dose(mg) 70 20 qd
B f 1
C f
u
0.007
D
E V
d
(L) 9
F
k (hr
-1
)
G T
1/2
(hr) 50
H %Cl
r
5
I %Cl
nr
95
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 21. Answers for Piroxicam

A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Quinidine (Problem 9 - 22)
Quinidine sulfate is used to treat ventricular and supraventricular arrythmias and is available in 200 and 300 mg tablets.
It is known to bind to -acid glycoprotein (AAG), which is an acute phase reactant. AAG rises in trauma, inflamation,
malignancy and stress and falls in hepatic disease, nephrotic syndrome and malneurtrition for example.(Use Qr = 72 L/
hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 22. Quinidine

A Dose(mg/kg) 10 10 TID
B f 0.7
C f
u
0.2 0.10 0.25 0.15 0.3
D s 0.83
E V
d
(L/kg) 2.6 2.0 2.75 2.2 3.0
F
k (hr
-1
)
G T
1/2
(hr) 6.4
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr/kg)
L
(L/hr/kg)
0.20
M
(L/hr/kg)
0.056
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
8
T N
U

MTC
1.7
V
W MEC
0.37
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 22. Answers for Quinidine

A Dose(mg) 10 10 10 10 10 5
FRR 1 1 0.5 1 1 1
FIR 1 1 0.25 0.5 0.75 1.5
FRH 1 1 1 1 0.5 1
FIH 1 1 0.5 1.25 0.75 0.5
B f 0.7
C f
u
0.20 0.10 0.25 0.15 0.30
D s 0.83
E V
d
(L) 2.6 2.0 2.75 2.2 3.0
F
k (hr
-1
)
0.098 0.057 0.101 0.087 0.061
G T
1/2
(hr) 7 12.1 6.9 7.9 11.3
H %Cl
r
22 12.3 10 22 46
I %Cl
nr
78 87.7 90 78 54
J AUC (mg/L*hr) 27.3 61.3 20.6 36.5 19.0
K (L/hr)
0.256 0.114 0.28 0.19 0.18
L
(L/hr)
0.20 0.10 0.25 0.15 0.1
M
(L/hr)
0.056 0.014 0.028 0.04 0.08
L 0.0021
O 0.00078
P
(L/hr)
1.0
Q
(L/hr)
0.28
R F
CL
1 0.45 1.1 0.75 0.72
S
(hr)
8 8 8 8 8
T N 1.3 0.66 1.16 1.0 0.71
U

MTC
1.7
0.82 0.79 0.95 0.79 0.75
V 0.57 0.63 0.65 0.56 0.59
W MEC
0.3
0.37 0.5 0.44 0.39 0.46
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Tazobactam (Problem 9 - 23)
Johnson, C., et. al., Single-dose pharmacokinetics of piperacillin and tazobactam in patients with renal disease, Clinical Phar-
macology and Therapeutics, Vol. 51, (1992), p. 32 - 41.
Tazobactam is an irreversible beta-lactamase inhibitor.
PROBLEM TABLE 9 - 23. Tazobactam
TABLE 9 - 23. Answers for Tazobactam
A Dose(mg) 375 IV 375 qid
B f 1
C f
u
0.96
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 0.89
H %Cl
r
68
I %Cl
nr
32
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
6
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Theophylline (Problem 9 - 24)
Wagner, J., Theophylline - pooled Michaelis-Menten parameters and implications, Clinical Pharmacokinetics, Vol. 10, (1985),
p. 432 - 442.
PROBLEM TABLE 9 - 24. Theophylline
A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 24. Answers for Theophylline

A Dose(mg)
B f
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Tolrestat (Problem 9 - 25)
Troy, S., et. al., The effect of renal disease on tolrestat pharmacokinetics, Clinical Pharmacology and Therapeutics, Vol. 51,
(1992), p. 271 - 277.
Tolrestat is an aldose reductase inhibitor used in the treatment of diabetic neuropathy, diabetic nephropathy, and dia-
betic retinopathy. (Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 25. Tolrestat
B f 0.8
C f
u
D
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr) 10.6
H %Cl
r
25
I %Cl
nr
40 bile 35 metab.
J AUC (mg/L*hr) 86
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 25. Answers for Tolrestat

A Dose(mg) 200 200 TID 200 TID 200 TID 200 TID 200 BID
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 1
FRH 1 1 1 1 0.5 1
FIH 1 1 1 1 1 0.5
B f 0.8
C f
u
1
E V
d
(L) 28.5
F
k (hr
-1
)
0.0654 0.057 0.057 0.065 0.041
G T
1/2
(hr) 10.6 12.1 12.1 10.7 16.9
H %Cl
r
25 14.3 14.3 25.3 39.8
I %Cl
nr
75 85.7 85.7 74.7 60.2
J AUC (mg/L*hr) 86 98.3 98.2 87 137
K (L/hr)
1.86 1.63 1.63 1.84 1.17
L
(L/hr)
1.4 1.4 1.4 1.4 0.7
M
(L/hr)
0.46 0.23 0.47 0.47 0.47
L 0.0155
O 0.0065
P
(L/hr)
1.42
Q
(L/hr)
0.47
R F
CL
1 0.88 0.88 0.99 0.63
S
(hr)
8 8 8 8 12
T N 0.75 0.66 0.66 0.75 0.71
U

13.8 15.3 15.3 13.9 14.4
V 10.8 12.3 12.3 10.9 11.4
W 8.2 9.6 9.7 8.3 8.8
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Vancomycin (Problem 9 - 26)
Macais, W., Meuller, B., and Scarim, S., Vancomycin pharmacokinetics in acute renal failure; preservation of nonrenal clear-
ance, Clinical Pharmacology and Therapeutics, Vol., 50, (1991), p. 688 - 694.
Vancomycin is a glycopeptide antibiotic used in the treatment of infections caused by Gram-positive organisms.
PROBLEM TABLE 9 - 26. Vancomycin
A Dose(mg) 1000 500 QID
B f 1
C f
u
D 0.44
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
70
I %Cl
nr
30
J AUC (mg/L*hr) 543
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 26. Answers for Vancomycin
A Dose(mg)
B f
C f
u
E V
d
(L)
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
M
(L/hr)
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
Xipamide (Problem 9 - 27)
Knauf, H, et. al., Xipamide disposition in liver cirrhosis, Clinical Pharmacology and Therapeutics, Vol. 48, No. 6, (1990), p. 328
- 632.
Xipamide is a diuretic that has been used in the treatment of congestive heart failure, hypertension, advanced renal fail-
ure, and hepatic edema.(Use Qr = 72 L/hr; Qh = 90 L/hr)
PROBLEM TABLE 9 - 27. Xipamide
A Dose(mg) 40 40 QID
B f 0.8
C f
u
0.01 0.01 0.02 0.01 0.025
E V
d
(L) 21
F
k (hr
-1
)
G T
1/2
(hr)
H %Cl
r
I %Cl
nr
J AUC (mg/L*hr)
K (L/hr)
L
(L/hr)
1.38
M
(L/hr)
0.72
L
O
P
(L/hr)
Q
(L/hr)
R F
CL
1
S
(hr)
T N
U

V
W
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Clearance
TABLE 9 - 27. Answers for Xipamide
A Dose(mg) 40 40 QID 40 QID 20 QID 40 QID 20 QID
FRR 1 1 0.5 1 1 1
FIR 1 1 0.5 0.5 1 2.5
FRH 1 1 1 1 0.5 1
FIH 1 1 1 2 1 0.5
B f 0.8
C f
u
0.01 0.01 0.02 0.01 0.025
E V
d
(L) 21
F
k (hr
-1
)
0.1 0.083 0.146 0.1 0.118
G T
1/2
(hr) 6.9 8.4 4.7 7.0 5.9
H %Cl
r
34 21 12 35 72
I %Cl
nr
66 79 88 65 28
J AUC (mg/L*hr) 15.2 18.4 7.8 15.4 6.5
K (L/hr)
2.1 1.74 3.1 2.1 2.5
L
(L/hr)
1.38 1.38 2.71 1.36 0.7
M
(L/hr)
0.72 0.36 0.36 0.72 1.8
L 0.0144
O 0.01
P
(L/hr)
140
Q
(L/hr)
73
R F
CL
1 0.83 1.46 1 1.18
S
(hr)
6 6 4 6 6
T N 0.87 0.71 0.847 0.86 1
U

0.034 0.039 0.034 0.034 0.038
V 0.025 0.031 0.026 0.025 0.027
W 0.019 0.024 0.019 0.019 0.019
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
CHAPTER 10 Dosage Regimen (Healthy,
Aged, and Diseased Patients)
OBJECTIVES
1. Given population average patient data, the student will devise (V) dosage regi-
mens which will maintain plasma concentrations of drug within the therapeutic
range.
2. Given specific patient information, the patient will justify (VI) dosage regimen
recommendations.
3. Given patient information regarding organ function, the student will devise (V)
and justify (VI) dosage regimen recommendations for the compromised patient.
4. The student will write (V) a professional consult using the above calculations
Dosage Regimen (Healthy, Aged, and Diseased Patients)
10.1 Therapeutic Drug Monitoring
10.1.1 THERAPEUTIC RANGE
The pharmacokinetics of a drug determine the blood concentration achieved from
a prescribed dosing regimen. During multiple drug dosing, the blood concentration
will reflect the drug concentration at the receptor site; and it is the receptor site
concentration that determines the intensity of the drugs effect. Therefore, in order
to predict a patients response to a drug regimen, both the pharmacokinetics and
pharmacological response characteristics of the drug must be understood.
There exists a fundamental relationship between drug pharmacokinetics and phar-
macologic response. The relationship between response and ln-concentration is
sigmoidal. A threshold concentration of drug must be attained befor any response
is ellicited at all. Therapy is accheived when the desired effect is attained because
the required concentration has been reached. That concentration would set the
lower limit of utility of the drug, and is called Effective Concentration (MEC).
Most drugs are not clean, that is exhibit only the desired therapeutic response.
They also exhibit undesired side effects, sometimes called toxic effects at a higher,
hopefully a lot higher, concentration. At some concentration, these toxic side
effects become become intollerable. That concentration, or one below it, would
set the upper limit of utility for the drug and is called the Maximum Therapeutic
Concentration or Minimum Toxic Concentration (MTC). Patient studies have
generated upper (MTC) and lower (MEC) plasma concentration ranges that are
deemed safe and effective in treating specific disease states. These concentrations
are known as the therapeutic range for the drug (see Table 10-1).When a drug is
administered at a fixed dosage to numerous subjects, the blood concentrations
achieved vary greatly due to biological variation. However it is possible to have a
reasomable
Clinically, digoxin concentrations below 0.8 will elicit a subtherapeutic
effect. Alternatively, when the digoxin concentration exceeds 2.0 side
effects occur (nausea and vomiting, abdominal pain, visual disturbances). Drugs
like digoxin possess a narrow therapeutic index because the concentrations that
ng ml
ng ml
may produce toxic effects are close to those required for therapeutic effects. The
importance of considering both pharmacokinetics and pharmacodynamics is clear.
Note that drug concentrations may be expressed by a variety of units.
Pharmacokinetic factors that cause variability in plasma drug concentration are:
Drug-drug interaction
patient disease state
physiological states such as age, weight, sex
drug absorption variation
differences in the ability of a patient to metabolize and eliminate the drug
If we were to give an identical dose of drug to a large group of patients and then
measure the highest plasma drug concentration we would see that due to individual
variability, the resulting plasma drug concentrations differ. This variability can be
attributed to factors influencing drug absorption, distribution, metabolism, and
excretion. Therefore, drug dosage regimens must take into account any disease
altering state or physiological difference in the individual.
Therapeutic drug monitoring optimizes a patients drug therapy by determining
plasma drug concentrations to ensure the rapid and safe drug level in the therapeu-
tic range.
TABLE 10-1. Average therapeutic drug concentration
DRUG RANGE
digoxin
0.8-2.0
gentamicin
2-10 l
lidocaine
1-4
lithium
0.4-1.4
phenytoin
10-20
phenobarbitol
10-30
procainamide
4-8
quinidine
3-6
theophylline
10-20
ng ml
g ml
g ml
mEq L
g ml
g ml
g ml
g ml
g ml
Two components make
up the process of
therapeutic drug
monitoring:
Assays for determination of the drug concentration in plasma
Interpretation and application of the resulting concentration data to develop a safe and effective
drug regimen.
The major potential advantages of therapeutic drug monitoring are the maximiza-
tion of therapeutic drug benefits and the minimization of toxic drug effects. The
formulation of drug therapy regimens by therapeutic drug monitoring involves a
process for reaching dosage decisions.
10.1.2 THERAPEUTIC MONITORING: WHY DO WE CARE?
The usefulness of a drugs concentration vs. time profile i based on the observation
that for many drugs there is a relationship between plasma concentration and ther-
apeutic response. There is a drug concentration below which the drug is ineffec-
tive, the Minimum Effective Concentration (MEC), and above which the drug has
untoward effects, the Minimum Toxic Concentration (MTC). That defines the
range in which we must attempt to keep the drug concentration (Therapeutic
Range).
The data in Table 10-1 are population averages. Most people respond to drug con-
centrations in these ranges. There is always the possibility that the range will be
different in an individual patient.
For every pharmacokinetic parameter that we measure, there is a population aver-
age and a range. This is normal and is called biological variation. People are differ-
ent. In addition to biological variation there is always error in the laboratory assays
that we use to measure the parameters and error in the time we take the sample.
Even with these errors, in many cases, he therapy is better when we attempt to
monitor the patients plasma concentration to optimize therapy than if we dont.
This is called therapeutic monitoring. If done properly, the plasma concentrations
are rapidly attained and maintained within the therapeutic range throughout the
course of therapy. This is not to say all drugs should be monitored. Some drugs
have a such a wide therapeutic range or little to no toxic effects that the concentra-
tions matter very little. Therapeutic monitoring is useful when:
a correlation exists between response and concentration
the drug has a narrow therapeutic range
the pharmacological response is not easily assessed
there is a wide inter-subject range in plasma concentrations for a given dose
In this era of DRGs, where reimbursement is no longer tied to cost, therapeutic
monitoring of key drugs can be economically beneficial to an institution. A recent
study (DeStache 1990) showed a significant difference with regard to days in the
hospital between the patients on gentamicin who were monitored (and their dosage
regulated as a consequence) vs. those who were not. With DRGs the hospital was
reimbursed a flat fee irrespective of the number of days the patient stayed in the
hospital. If the number of days cost less than what the DRG paid, the hospital
makes money. If the days cost more than the hospital loses money. This study
showed that if all patients in the hospital who were on gentamicin were monitored,
the hospital would save $4,000,000. Thats right FOUR MILLION per year. I
would say that would pay my salary, with a little left over, and that is only one
drug!
The process of
therapeutic monitoring
takes effort.
First the MD must order the blood assays.
Second, someone (nurse, med tech, you) must take the blood.
Someone (lab tech, you) must assay the drug concentration in the blood.
You must interpret the data
You must communicate your interpretation and your recommendations for dosage regimen
change to the MD. This will allow for informed dosage decisions.
You must follow through to ensure proper changes have been made.
You must continue the process throughout therapy. Therapeutic monitoring, in many cases, will
be part of your practice. It can be very rewarding
Thus, if we have deterimined the therapeutic range, we could use pharmacokinet-
ics to determine the optimum dosage regemin to maintain the patients plasma con-
centration within that range.
10.1.3 STEADY STATE
It is rare that a drug is given only once. Most therapies consist of multiple doses
of several days duration, if not several years. It is necessary, therefore, to be able
to asess plasma concenterations, both the peak which much be at or below the
MTC and the trough which must be at or above the MEC for the drug to be effec-
tive under these conditions. Thus when we dose a patient, the concentration pro-
file must be within the Therapeutic Range during the entire time that the patient is
taking the drug. We can calculate the plasma concentrations in the followin man-
ner. In the simplest model, suppose we give a drug by IV Bolus (because the math
is simpler). The equation which would result be
I.V. Bolus Multiple Dose (EQ 10-1)
The peak would be
Cp Cp
0
e
kt ( ) D
V
---- e
kt ( )
,
_
= =
(EQ 10-2)
If we allowed the drug to be eliminated for hours, the trough would be:
(EQ 10-3)
Upon giving a second dose, prior to the complete removal by the body of the first
dose the would be the second dose plus what was left from the first dose:
(EQ 10-4)
and the would be times , thus:
: (EQ 10-5)
After n doses, the would be:
(EQ 10-6)
while the would be:
(EQ 10-7)
Subtracting equation 10-7 from equation 10-6 to eliminate the series yields:
(EQ 10-8)
is also which means that
(EQ 10-9)
Equating equation 10-8 and equation 10-9 and solving for yields:
(EQ 10-10)
At large n, and thus the steady state maximum, , is:
Cp
max
1 D
V
---- =
Cp
min
1 D
V
---- e
k ( ) ( )
=
Cp
max
2
Cp
max
2 D
V
----
D
V
---- e
k ( ) ( )
,
_
+ =
Cp
min
2
Cp
max
2
e
k ( ) ( )
Cp
min
2 D
V
---- e
k ( ) ( )
D
V
---- e
2k ( ) ( )
,
_
+ =
Cp
max
n
Cp
max
n D
V
----
D
V
---- e
k ( ) ( )
D
V
---- e
n 1 ( ) k ( ) ( )
+ + + =
Cp
min
n
Cp
min
n D
V
---- e
k ( ) ( )
D
V
---- e
2k ( ) ( )
,
_
D
V
---- e
nk ( ) ( )
+ + + =
Cp
max
n
Cp
min
n
D
V
----
D
V
---- e
nk ( ) ( )
,
_
D
V
---- 1 e
nk ( )
( ) = =
Cp
min
n
Cp
max
n
e
k ( )
Cp
max
n
Cp
min
n
Cp
max
n
Cp
max
n
e
k ( )
Cp
max
n
1 e
k ( )
( ) = =
Cp
max
n
Cp
max
n D
V
----
1 e
nk ( )
1 e
k ( )
---------------------------- =
e
nk ( )
0 Cp
max
ss
(EQ 10-11)
and the steady state minimum, , is :
(EQ 10-12)
In order to make a general equation set from equation 10-11 and equation 10-12,
let N be the number of half lives in a dosing interval, , and
. Substituting into the function , yields and
thus equation 10-11 becomes:
(EQ 10-13)
and equation 10-12 becomes :
(EQ 10-14)
The average drug concentration under these conditions would be equivalant to the
steady state concentration attained by an infusion of the same rate, i.e. if we were
to give a multiple dose at 200 mg every four hours (q4h) or 400 mg every eight
hours (q8h), the average that would be attained would be equivelaent to the steady
state plasma concentration attained by giving an infusion at 50 mg/hr, (Q = 50 mg/
hr), and thus, in the infusion, the and in multiple dosing , and
so:
(EQ 10-15)
Oral Multiple Dosing
(Approximation)
Similar equations, although more complex, can be derived for multiple dose oral
products. However, if we were agreed to live with some error these equations, with
some modifications could be used to approximate multiple dose oral products.
The error on both calculated and would be in the direction of
safety, i.e. the calculated would be higher and the calculated would
be lower that their respective multiple dose oral calculations. Thus, if the simpler
Cp
max
ss D
V
----
1
1 e
k ( )
------------------------- =
Cp
min
ss
Cp
min
ss D
V
----
e
k ( )
1 e
k ( )
------------------------- =
N

t
1 2
--------- =
k 2 ( ) ln ( ) t
1 2
= e
k ( )
e
k ( ) 1
2
---
,
_
N
=
Cp
max
ss D
V
----
1
1
1
2
---
,
_
N
--------------------- =
Cp
min
ss D
V
----
1
2
---
,
_
N
1
1
2
---
,
_
N
--------------------- =
Cp
ss Q
k V
---------- = Q
D
---- =
k 0.693 N =
Cp
ss
avg
D
V K
-------------------
D
V 0.693 N
------------------------------
1.443 D
N V
---------------------- = = =
Cp
max
ss
Cp
min
ss
Cp
max
ss
Cp
min
ss
equations place the and within the Therapeutic Range, the oral multi-
ple dose equations would also. The two modifications would be to the Dose. Bio-
availability, f, must be considered, and if the drug given is not the drug measured in
the blood, the salt factor, S, the difference in the molecular weight of the two com-
pounds must be taken into account, (i.e. ). Thus, when amino-
phyline, which is a complex consisting of two theophyline molecules and an
ethylinedyamine molecule is given, but theophyline is measured, the salt factor,
. Thus for oral multiple dose, we can approximate
for
using IV bolus equations as such :
(EQ 10-16)
(EQ 10-17)
(EQ 10-18)
because errors involved with this approximation both in maximum and minimum
calculations (peak and trough) place the drug further within the Therapeutic
Range, i.e. the real peaks are lower than the calculated peaks and the real troughs
are higher than the calculated troughs, thus both errors are on the side of safety.
Dosing Interval The object of pharmacokinetics is to optimize therapy. By definition, that is to
maintain the plasma concentration of the drug within the therapeutic range for the
duration of the therapy presuming that is needed. Thus, the concentrations must
stay within the MTC and MEC or
(EQ 10-19)
by deviding equation 10-18 into equation 10-16 and simplifying. Given these lim-
its, the maximum dosing interval, , is obtained by solving for N
max
:
Cp
max
ss
C
min
ss
S
MW
measured
MW
given
------------------------------- =
S
MW
Theo
MW
Amino
------------------------
2 180.17
420.44
------------------------ 0.857 = = =
Cp
max
ss S f D
V
------------------
1
1
1
2
---
,
_
N
--------------------- =
Cp
ss
avg
S f D
V K
-------------------
S f D
V 0.693 N
------------------------------
1.443 S f D
N V
------------------------------------ = = =
Cp
min
ss S f D
V
------------------
1
2
---
,
_
N
1
1
2
---
,
_
N
--------------------- =
MTC
MEC
-------------
Cp
max
ss
Cp
min
ss
------------------- 2
N
max
= =
max
(EQ 10-20)
and since by definition,
(EQ 10-21)
is not necessarily the dosing interval of choice, but it is the maximum dosing
interval attainable without sustained or controlled release delivery systems.
Accepable dosing intervals are those which result in a dose being given at the same
time of the day, every day. Imagine, if you will, the chaos on the nursing floor if
the dose for a given drug were every 15 hours. Compliance, none too high when
the patient is given a reasonable dosing interval, would go straight to the toilet if
we asked the patient to take a tablet every 5.3 hours. What would be optimal would
be to tie the takeing of the drug with an activity that occurs the same time every
day for once a day therapy, or at least dose the same time every day. Thus, for
multiple daily doses, the only regimens that work are those which when devide
into 24 hours give unit answers: QD = 24/1 = q24h; BID = 24/2 = q12h, TID = 24/
3 = q8h; QID = 24/4 = q6h; q4h; q3h; q2h. These result in decreasing orders of
patient compliance (unless the patient is really motivated to take the drug every 2
hours - forget it.) Thus the maximum acceptable dosing interval would be the larg-
est acceptable dosing interval below the . So, for example if is 15.7
hours, the maximum acceptable dosing interval would be 12 hours. we could also
dose every 8, 6 or 4 hours if necessary.
N
max
Ln
MTC
MEC
-------------
,
_
Ln2
-------------------------- =
N
max
max
t
1 2
----------- =
max
N
max
t
1 2
=
max
max

max
10.2 Diseases - Dosing the Compromised Patient
As previously discussed in the chapter on clearance, diseases result in changes in
clearance. These are routinely as a consequence of changes in organ function or
blood flow to the organ. Diseases which cause a change in clearance, do so by
changing either the elimination rate constant, K, or the volume of distribution, V
d
,
or both. Thus the fractional change in total body clearance :
(EQ 10-22)
Where X* indicates new or changed variable. In general, if ,
changes in dosage regimen are not necessary. In order to return a previously con-
trolled healthy pateint back to the therapeutic range, a general rule of thumb is sug-
gested as an initial starting point. The desease modifies K (as t
1/2
) and V. As
pharmacists, we can modify D and . These variables are paired in the above
equations (equation 10-16 and equation 10-18), D with V (in ) and
with (in ). If the physiological change is a change in V, the pharmacist
would recommend a change in D proportionally, and if the half life changes, the
pharmacist would recommend a change in the dosing interval proportionally.
Remenber, the object is to get the plasma concentrations back to where they were
prior to the illness. The only problem is that we are limited to these recommended
changes being incremental and not continuous. That is a change in dose is limited
to the available dosage forms and strengths and a change in dosing interval is
limeted to the accepatable dosing interval.
Protein Binding If the drug is highly protein bound, the object would be to get the free concentra-
tion back to what it was prior to illness. Consequently, equation 10-16, equation
10-17, and equation 10-18 would be rewritten thus:
(EQ 10-23)
(EQ 10-24)
F
Cl
tot
Cl
tot
Cl
tot
--------------
K
K V
------------------ = =
0.80 F
Cl
t ot
1.2 < <
S f D
V
------------------ t
1 2
N

t
1 2
--------- =
Cp
ss
max
free
f
u
Cp
ss
max
f
u
S f D
V
--------------------------
1
1
1
2
---
,
_
N
-------------------- = =
Cp
ss
avg
free
f
u
C = p
ss
avg
f
u
S f D
V K
--------------------------
f
u
S f D
V 0.693 N
------------------------------ = =
(EQ 10-25)
Some interesting and unexpected things result from these relationships. Since
plasma or blood concentrations are usually measured, if a drug is highly protein
bound and the desease results in upsetting that equilibrium, you might see toxicity
resulltling from normal or even subtherapeutic measured concentrations. More on
that in the chapter on protein binding.
Cp
ss
min
free
f
u
C p
ss
min
f
u
S f D
V
--------------------------
1
2
---
,
_
N
1
1
2
---
,
_
N
-------------------- = =
10.3 Problems
Alprazolam (Problem 10 - 1)
Juhl, R. et al., "Alprazolam pharmacokinetics in alcoholic liver disease", Journal of Clinical Pharmacology, Vol.24, (1984), p. 113
- 119.
Alprazolam is an anti-anxiety agent which is metabolized to 4-hydroxy and -hydroxy metabolites. In this
study, patients with cirrhosis of the liver and healthy patients were each given doses of 1.0 mg of Alpra-
zolam. The following data is for healthy patients.
Assume that your patient weighs 70 kg when answering the following:
1. Find k.
2. Find the MRT.
3. Find the .
4. Find the AUMC.
5. Find .
6. What is N?
7. What is the patient's maximum plasma concentration, , under this dosage regimen.
8. What is the patient's average plasma concentration, , under this dosage regimen.
9. What is the patient's minimum plasma concentration, , under this dosage regimen.
PROBLEM TABLE 10 - 1. Alprazolam
Dose 1.0 mg BID
1.16 L/kg
1.22
AUC
529.3
Cefixime (Problem 10 - 2)
Faulkner, R. et al., "Pharmacokinetics of cefixime after once-a-day and twice-a-day dosing to steady state", Journal of Clinical
Pharmacology, Vol.27, (1987), p. 807 - 812.
Cefixime is a broad-spectrum cephalosporin which is active against a variety of gram positive and gram negative bac-
teria. In this study, patients received a 200 mg oral dose of cefixime twice daily.
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 2. Cefixime
Dose 200 mg BID
3.3 hours
286
32
AUC 14.12
Cefpodoxime (Problem 10 - 3)
Borin, M. et. al., "Pharmacokinetics and tolerance studies of cepodoxime after single-and multiple-dose oral administration of cef-
podoxime proxetil", Journal of Clinical Pharmacology, Vol.31, (1991), p. 1137 - 1145.
Cefpodoxime proxetil is a third-generation, broad-spectrum cephalosporin which is given by the oral route. It is a pro-
drug which is converted in vivo to cefpodoxime which inhibits bacterial cell wall synthesis by binding to penicillin-
binding proteins.
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 3. Cefpodoxime
Dose 100 mg BID
2.1 hours
271
79.1
AUC 6.9
Cefprozil (Problem 10 - 4)
Lode, H. et. al., "Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteers", Antimicrobial
Agents and Chemotherapy, Vol.36, (1992), p. 144 - 149.
Cefprozil is a broad-spectrum cephalosporin which is given by the oral route. In this study subjects received 500 mg
doses of cefprozil every twelve hours for eight days.
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 4. Cefprozil
Dose 500 mg q. 12 hours
55.11minutes
310.25
277.50
AUC 27.80
Clobazam (Problem 10 - 5)
Greenblatt, D. et. al., "Reduced single-dose clearance of clobazam in elderly men predicts increased multiple-dose accumulation",
Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94.
Clobazam is an agent used in the treatment of anxiety. In this study, patients received 10 mg dose of clobazam daily.
1. Find k.
2. Find MRT.
3. Find the ?
4. Find the AUMC.
5. Find .
6. What is N?
10. Your patients renal function drops to 50% of normal. What would be a new dosing regimen under these condi-
tions? (Assume that you want to keep < 110% of the normal and that you want to keep > 90% of the normal .)
PROBLEM TABLE 10 - 5. Clobazam
Dose 10 mg daily
180 hours
AUC
Maloprim (Problem 10 - 6)
Edstein, M., Rieckmann, K., and Veenendaal, J., "Multiple-dose pharmacokinetics and in vitro antimalarial activity of dapsone
plus pyrimethamine (Maloprim) in man", British Journal of Clinical Pharmacokinetics, Vol.30, (1990), p.259 - 265.
Maloprim is an agent which contains both dapsone and pyrimethamine. In this study, healthy volunteers
were given 100 mg of dapsone plus 12.5 mg pyrimethamine weekly. The following data is for dapsone:
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 6. Maloprim
Dose 100 mg weekly
22.6 hours
AUC 35.0
Doxycycline (Problem 10 - 7)
Shmuklarsky, M. et. al., "Failure of doxycycline as a causal prophylactic agent against Plasmodium falciparum malaria in healthy
nonimmune volunteers", Annals of Internal Medicine, Vol.120, (1994), p. 294 - 298.
Doxycycline is an antibiotic which has been recommended for prevention of malaria in people traveling to areas
endemic to chloroquine-resistant P. falciparum malaria who are unable to take mefloquine. This study determined that
doxycycline is not effective for this use. Volunteers were given 100 mg doses of doxycycline daily for 10 days.
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 7. Doxycycline
Dose 100 mg daily
21.9 hours
AUC 40.7
DQ-2556 (Problem 10 - 8)
Nakashima, M. et. al., "Phase I study of DQ-2556, a new parenteral 3-quaternary ammonium cephalosporin antibiotic", Journal of
Clinical Pharmacology, Vol.33, (1993), p. 57 - 62.
DQ-2556 is a new broad-spectrum cephalosporin which is active against many bacteria including Pseudomonas aerug-
inosa. Subjects in this study were each given a 2000 mg infusion of DQ-2556 over 5 minutes every 12 hours for a total
of 9 doses.
1. Find Cl.
2. Find k.
3. Find the MRT.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 8. DQ-2556
Dose 2000 mg infusion over 5 minutes
17.6 L
8.5
7.1
AUC 241.0
Erythropoetin (Problem 10 - 9)
Gladziwa, U., et al., "Pharmacokinetics of epoetin (recombinant human erythropoietin) after long term therapy in patients under-
going haemodialysis and haemofiltration", Clinical Pharmacokinetics, Vol.8, (1983), p. 83 - 94.
Erythropoetin is a regulatory hormone of red blood cells. In this study patients with end-stage renal disease were given
150 U/kg of epoetin three times a week.
Assuming that your patient weighs 65 kg, please determine the following:
1. Find k.
2. Find MRT.
3. Find the .
4. Find the AUC.
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 9. Glipizide
Dose 150 U/kg t.i.w.
7.7hours
Cl 5.4
Flecainide (Problem 10 - 10)
Forland, S. et al., "Flecainide pharmacokinetics after multiple-dosing in patients with impaired renal function", Journal of Clinical
Flecainide acetate is a class 1C anti-arrhythmic agent which is used in the treatment of ventricular and supraventricular
arrhythmias. In this study, subjects were given doses of 100mg of flecainide orally twice daily.
Assume that your patient weighs 70 kg when calculating the following:
1. Find Cl.
2. Find k.
3. Find the MRT.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 10. Flecainide
Dose 100 mg BID
7.4 L/kg
486
89
AUC 3.429
Glipizide (Problem 10 - 11)
Kradjan, W. et al., "Glipizide pharmacokinetics: effects of age, diabetes, and multiple dosing", Journal of Clinical Pharmacology,
Vol.29, (1989), p. 1121 - 1127.
Glipizide is a second-generation oral hypoglycemic agent used in the treatment of non-insulin-dependent (type II) dia-
betes. In this study, both diabetic and non-diabetic elderly men were each given doses of 2.5 mg of glipizide daily for
five days. The data for the non-diabetic group is given below.
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 11.
Dose 2.5 mg daily
4.0 hours
0.47
AUC 2325.4
Lomefloxacin (Problem 10 - 12)
Hunt, T. and Adams, M., "Pharmacokinetics and safety of lomefloxacin following multiple doses", Diagn Microbiol Infect Dis,
Vol.12, (1989), p. 181 - 187.
Lomefloxacin is a quinolone antibiotic which is useful against both Gram-positive and Gram-negative bacteria. It is
used in the treatment of urinary tract infections and lower respiratory tract infections. A dose of 400 mg of lomefloxa-
cin was given twice daily to healthy patients.
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 12. Lomefloxacin
Dose 400 mg BID
7.32 hours
AUC 61.67
Loratadine (Problem 10 - 13)
Radwanski, E. et al., "Loratadine: multiple-dose pharmacokinetics", Journal of Clinical Pharmacology, Vol.27, (1987), p. 530 -
533.
Loratadine is an antihistamine which is orally active. In this study, healthy, male volunteers were each given a 40-mg
loratadine capsule daily for ten days.
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 13. Loratadine
Dose 40 mg daily
14.4 hours
AUC 96.0
Methamphetamine (Problem 10 - 14)
Cook, C., et al., "Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humans", Drug Metabolism
and Disposition, Vol.20, (1992), p. 856 - 861.
Methamphetamine is a CNS stimulant which is used in the treatment of attention deficit disorder and obesity. In this
study, subjects were given a 0.125 mg/kg dose of methamphetamine daily.
Assume that your patient weighs 70 kg when calculating the following:
1. Find k.
2. Find MRT.
3. Find the .
4. Find the AUC.
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 14. Methamphetamine
Dose 0.125 mg/kg daily
8.46 hours
65.0
212
Mexiletine (Problem 10 - 15)
Gillis, A. and Kates, R., "Clinical pharmacokinetics of the newer antiarrhythmic agents", Clinical Pharmacokinetics, Vol.9, (1984),
p. 375 - 403.
Mexiletine is a class Ib antiarrhythmic agent. In this study, volunteers each received a 1600 mg dose orally each day.
1. Find k.
2. Find the MRT.
3. Find the .
4. Find the AUC.
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 15. Mexiletine
Dose 1600 mg daily
380 L
681
Moxisylyte (Problem 10 - 16)
Costa, P. et al., "Multiple-dose pharmacokinetics of moxisylyte after oral administration to healthy volunteers", Journal of Phar-
maceutical Sciences, Vol.82, (1993), p. 968 - 971.
Moxisylyte is an -adrenergic blocker which has been used in Europe for some times as a vasodilator in the
treatment of such disease states as age-associated mental impairment, acrocyanosis, Raynaud's syn-
drome, vascular cochlearvestibular disorders, glaucoma, and benign prostatic hyperplasia.
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 16. Moxisylyte
Dose 240 mg BID
2.28 hours
AUC 11186
Naproxen (Problem 10 - 17)
Ouweland, F. et. al., "Hypoalbuminaemia and naproxen pharmacokinetics in a patient with rheumatoid arthritis", Clinical Phar-
macokinetics, Vol.11, (1986), p. 511 - 515.
The pharmacokinetics parameters of naproxen were looked at in patients with rheumatoid arthritis in this study. A
patient received a dose of 500 mg of naproxen orally twice daily.
1. Find Cl.
2. Find k.
3. Find the MRT.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 17. Naproxen
Dose 500 mg BID
9.0 L
AUC 1134
Nisoldipine (Problem 10 - 18)
Harten, J. et al., "Influence of renal function on the pharmacokinetics and cardiovascular effects of nisoldipine after single and
multiple dosing", Clinical Pharmacokinetics, Vol.16, (1989), p. 55 - 64.
Nisoldipine is a second-generation calcium-channel blocker which is under investigation for use as an anti-hyperten-
sive agent. Nisoldipine is mainly eliminated through liver metabolism with metabolites being excreted mainly in the
urine but also in the feces. The systemic clearance of nisoldipine depends greatly on liver blood flow.
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the ?
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 18. Nisoldipine
Dose 10 mg BID orally
7.9 hours
AUC 5.2
Pefloxacin (Problem 10 - 19)
Bruno, D. et al., "Bayesian versus NONMEM estimation", , Vol. , (19 ), p. 657 - 668.
Pefloxacin is an antibiotic used to treat patients who are in the intensive care unit. For this study, patients were given a
400 mg dose of pefloxacin twice daily for eight days.
1. Find k.
2. Find MRT.
3. Find the ?
4. Find the AUC.
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 19. Pefloxacin
Dose 400 mg BID
21.3 hours
Cl 3.77
Phenylpropanolamine (Problem 10 - 20)
Scherzinger, S., Rowse, R., and Kanfer, I., "Steady state pharmacokinetics and dose-proportionality of phenylpropanolamine in
healthy subjects", Journal of Clinical Pharmacology, Vol.30, (1990), p. 372 - 377.
Phenylpropanolamine is a sympathomimetic agent which is used both for its action as a nasal decongestant and its
action as an anorexiant. In this study healthy volunteers were given doses of 25 mg every four hours for a total of
seven doses. It was found that phenylpropanolamine is 77% renally excreted.
1. Find k.
2. Find MRT.
3. Find Cl.
4. Find the AUC.
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 20. Phenylpropanolamine
Dose 25 mg q. 4 hours
4.71 hours
4.08 L/kg
0.5
Promethazine (Problem 10 - 21)
Taylor, G. and Houston, J., "Changes in the disposition of promethazine during multiple dosing in rabbits", Journal of Clinical
Promethazine is an agent used as an anti-histamine and a sedative. In this study rabbits weighing 2.7 to 3.3 kilograms
each received a 10 mg/kg dose of promethazine every 24 hours for 14 days.
1. Find k.
2. Find MRT.
3. Find the ?
4. Find the AUC.
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 21. Promethazine
Dose 10 mg/kg
249 minutes
65.0
Rufloxacin (Problem 10 - 22)
Mattina, R. et al., "Pharmacokinetics of rufloxacin in healthy volunteers after repeated oral doses", Chemotherapy, Vol.37, (1991),
p. 389 - 397.
Rufloxacin is a broad-spectrum, fluoroquinolone antibiotic. In this study a patient was given a loading dose of 300 mg
of rufloxacin followed by 150 mg of rufloxacin daily for five days.
1. Find k.
2. Find the MRT.
3. Find the .
4. Find the AUMC.
5. Find .
6. What is N?
PROBLEM TABLE 10 - 22. Rufloxacin
Dose 150 mg daily
104 L
41
10
AUC 121.5
Velnacrine (HP 029) (Problem 10 - 23)
Puri, S. et al., "Multiple dose pharmacokinetics, safety, and tolerance of velnacrine (HP 029) in healthy elderly subjects: a poten-
tial therapeutic agent for Alzheimer's disease", Journal of Clinical Pharmacology, Vol.30, (1990), p. 948 - 955.
Velnacrine is an investigative agent which has central cholinergic action and may be beneficial in the treatment of
Alzheimer's disease. Healthy, elderly, men were given doses of 100 mg twice daily in this study. It was found that 30%
of the velnacrine dose was excreted unchanged.
1. Find k.
2. Find the MRT.
3. Find Cl.
4. Find the .
5. Find the AUMC.
6. Find .
7. What is N?
PROBLEM TABLE 10 - 23. Velnacrine (HP 029)
Dose 100 mg BID
2.4 hours
AUC 809.5
10.4 Answers
Alprazolam
1. 0.0631 h-1
2. 15.85 hours
3. 10.98 hours
4. 8387.81
5. 12
6. 1.093
7. 23.19
8. 16.26
9. 10.876
Cefixime
1. 0.210 h-1
2. 4.76 hours
3. 14.164 L/h
4. 67.435 L
5. 62.224
6. 12
7. 3.64
8. 3.225
9. 1.177
10. 0.259
Cefpodoxime
1. 0.330 h-1
2. 3.03 hours
3. 14.49 L/h
4. 43.91 L
5. 20.905
6. 12
7. 5.714
8. 2.322
9. 0.575
10. 0.0442
Cefprozil
1. 0.0126 min-1
2. 76.51 minutes
3. 17.99 L/h
4. 23.83 L
5. 36.84
6. 12
7. 13.065
8. 20.98
9. 2.317
10. 2.45
Maloprim
1. 0.0307 h-1
2. 32.6 hours
3. 2.857 L/h
4. 93.16 L
5. 1141.17
6. 168
7. 7.435
8. 1.08
9. 0.208
10. 6.25
Doxycycline
1. 0.0317 h-1
2. 31.595 hours
3. 2.457 L/h
4. 77.629 L
5. 1285.92
6. 24
7. 1.096
8. 2.42
9. 1.696
10. 1.133
DQ-2556
1. 8.299 L/h
2. 0.4715 h-1
3. 2.12 hours
4. 1.47 hours
5. 511.11
6. 12
7. 8.163
8. 114
9. 20.083
10. 0.398
Erythropoetin
1. 0.09 h-1
2. 11.11 hours
3. 3599.24 mL
4. 30092.6
5. 334291.14
6. 72
7. 9.35
8. 2713.24
9. 417.98
10. 4.156
Glipizide
1. 0.173 h-1
2. 5.77 hours
3. 1.075 L/h
4. 6.204 L
5. 13419.37
6. 24
7. 6
8. 0.4094
9. 96.893
10. 6.396
Flecainide
1. 29.16 L/h
2. 0.0563 h-1
3. 17.76 hours
4. 12.31 hours
5. 60.91
6. 12
7. 0.975
8. 0.393
9. 0.286
10. 0.200
Lomefloxacin
1. 0.0947 h-1
2. 10.56 hours
3. 6.486 L/h
4. 68.497 L
5. 651.27
6. 12
7. 1.639
8. 8.6
9. 5.139
10. 2.76
Loratadine
1. 0.0481 h-1
2. 20.77 hours
3. 416.67 L/h
4. 8656.17 L
5. 1994.38
6. 24
7. 1.67
8. 6.746
9. 4
10. 2.125
Methamphetamine
1. 0.082 h-1
2. 12.21 hours
3. 46.7 L
4. 2.244
5. 27.383
6. 24
7. 2.837
8. 213.74
9. 93.48
10. 29
Moxisylyte
1. 0.304 h-1
2. 3.29 hours
3. 0.0215 L/h
4. 70.574 mL
5. 36794.61
6. 12
7. 5.263
8. 3.492
9. 0.9322
10. 0.0909
Naproxen
1. 0.441 L/h
2. 0.049 h-1
3. 20.412 hours
4. 14.149 hours
5. 23147.21
6. 12
7. 0.848
8. 124.98
9. 94.5
10. 69.43
Mexiletine
1. 0.1075 h-1
2. 9.3 hours
3. 6.45 hours
4. 39.16
5. 364.17
6. 24
7. 3.723
8. 4.256
9. 1.632
10. 0.345
Nisoldipine
1. 0.0877 h-1
2. 11.397 hours
3. 1923.08 L/h
4. 21.92 mL
5. 59.27
6. 12
7. 1.52
8. 700.7
9. 433.3
10. 244.5
Pefloxacin
1. 0.0325 h-1
2. 30.73 hours
3. 115.85 L
4. 106.1
5. 3260.4
6. 12
7. 0.563
8. 10.68
9. 8.84
10. 7.23
Phenylpropanolamine
1. 0.147 h-1
2. 6.795 hours
3. 36.03 L/h
4. 0.694
5. 4.715
6. 4
7. 0.849
8. 229.5
9. 173.5
10. 127.4
Promethazine
1. 0.167 h-1
2. 5.987 hours
3. 70.05 L
4. 2.56
5. 15.35
6. 24
7. 5.78
8. 436.19
9. 106.84
10. 7.92
Rufloxacin
0.0237 h-1
42.28 hours
29.30 hours
5136.6
24
0.819
3.33
2.54
1.89
Velnacrine
1. 0.289 h-1
2. 3.462 hours
3. 123.53 L/h
4. 427.73 L
5. 2802.87
6. 12
7. 5
8. 241.33
9. 67.46
10. 7.54
CHAPTER 11 Multicompartment Modeling
OBJECTIVES
1. This chapter is not completed.
Multicompartment Modeling
11.1 Executive Summary
11.2 Equations
11.3 PHARMCOKINETICS: MAMMILLARY MODELS
For many drugs the equilibrium between drug concentrations in different tissues is
not achieved rapidly. Thus, one of the assumptions of the one-compartment open
model sometimes becomes invalid. A more complex mammillary open model is
often necessary to describe mathematically the plasma concentration data (for
example) seen after the administration of some drugs. The simplest mammillary
open model is a two-compartment open model: for example:
Compartment One (central compartment) can be sampled through the blood (or
plasma, or serum). It may consist of organs or tissues which, being highly perfused
with blood, are in rapid equilibrium distribution with the blood.
Compartnent Two (peripheral compartment) cannot normally be sampled. It may
consist or organs or tissues which, being poorly perfused with blood, are in slow
equilibrium distribution with the blood.
The Body is the sum of both compartments.
1. Biexponential Properties of Two-Compartment Open Model
Following an intravenous bolus injection, the plasma concentration against time
profile has two phases:
a. Initial phase - ( - phase)
b. Terminal phase - ( - phase)
On semilogarithmic paper the terminal phase is linear, indicating that initial distri-
bution has been completed and that equilibrium has been attained. The terminal
half-life ( ) can be measured from the terminal phase.
2. Intravenous Bolus Administration: Plasma Concentration Data
For a one-compartment open model,
(EQ 10-26)
i.e., the concentration of drug in the plasma declines exponentially with time
For a two-compartment open model,
t
1 2
C
p
C
p
( )
o
e
kt
=
(EQ 10-27)
i.e., the concentration of drug in the plasma declines biexponentially with time
2.1 Symbols
and are intercept constants
and are hybrid rate constants
is the apparent volume of unchanged drug distribution in compartment one
, are micro rate constants
2.2 Relationships (for reference, except Eq. 3)
C
p
A
1
e
t
B
1
e
t
+ ( ) =
A
1
B
1
M L
3
( )
T
1
( )
V
1
L
3
( )
k
10
k
12
and , , k
21
T
1
( )
0.5 k
10
k
12
k
21
+ + ( ) k
10
k
12
k
21
+ + ( )
2
4k
10
k
12
+ [ ] =

(EQ 10-28)
2.3 Obtaining Pharmacokinetic Parameters by Feathering
By convention, >
a. Plot against t on semilogarithmic paper
b. Find from the linear terminal phase: see Intravenous Administration,
section A1.4a
c. Calculate the terminal hybrid rate constant ; in reality it contains both dis-
tributive ( and ) and elimination factors.
(EQ 10-29)
0.5 k
10
k
12
k
21
+ + ( ) k
10
k
12
k
21
+ + ( )
2
4k
10
k
12
[ ] =
A
1
D
V
1
------
k
21
( )
( )
---------------------- =
B
1
D
V
1
------
k
21
( )
( )
--------------------- =
A
1
B
1
C
p
( )
o
= +

C
p
t
1 2
( )
k
12
k
21
k
10
( )
0.693
t
1 2
------------- =
d. Draw a straight line through the linear terminal elimination phase and extralpo-
late this line to t = 0. The intercept is equal to .
e. Read estrapolated plasma concentrations from the plot at times equal to
those given for values of which are prior to the terminal phase.
f. At each of these times calculate:
g. Plot against t (see Eq.8) on semilogarithmic paper. The is a feath-
ered line and should decline linearly.
h. Find the half-life of the plot. It wil refer to the initial phase. Calculate,
i. Measure the intercept of the feathered line; it will equal to (Note that usu-
ally , even theoetically).
B
1
C
p
( )
C
p
C
p
( )
diff
C
p
C
p
=
C
p
( )
diff
0.693
half life
------------------------- =
A
1
A
1
B
1
=
j. Calculate from Eq. 3
k. Calcultate by
(EQ 10-30)
.
Theory
When t is large, < . Hence, Eq. 2 becomes
(EQ 10-31)
i.e., when t is large, the concentration of the drug in the plasma declines exponen-
tilly with time.
The extrapolated plasma concentrations are
(EQ 10-32)
Substituting from Eqs. 2 and 7a into Eq. 5,
C
p
( )
o
V
1
V
1
X
o
C
p
( )
o
-------------
D
A
1
B
1
+
------------------ = =
e
t
e
t
C
p
B
1
e
t
=
C
p
B
1
e
t
=
(EQ 10-33)
i.e., the difference between observed and extrapolated drug concentrations in the
plasma declines exponentially with time.
Note (for reference only)
It is usually not informative to determine the microrate constant; but see one use
under the note on dosage regimens.

2.4 Clearance and Volume
If model-independant equations can be used to define these terms, this is preferred.
a. Systemic Clearance (Cl) may be calculated by,
C
p
( )
diff
A
1
e
t
=
k
21
B
1
A
1
+
A
1
B
1
+
-------------------------- =
k
10
k
21
=
k
12
k
10
k
21
+ =
(EQ 10-34)
b. The volume terms are complex than in a one-compartment open model. There
are two terms of interest:
The apparent volume of distribution in compartment one
This is calculated using Eq. 6.
The apparent volume of distribution at pseudo-distribution equilibrium
This volume may be defined only in relation to the terminal phase ( phase), when
initial distribution has been completed.
As requires calculation of the total area under the plasma concentration against
time curve it is sometimes known as .
c. Comparing Eqs. 9 and 10,
(EQ 10-35)
Cl
D
AUC ( )
o
----------------------- =
V
1
( )
V
( )
D
AUC ( )
o
--------------------------- =
V
V
area
Cl V
=
It may also be shown that,
(EQ 10-36)
This follows as systemic clearance is always given by the elimination rate constant
out of the body multiplied by the apparent volume of distribution in the compart-
ment from which drug leaves the body. Comparing Eqs. 11 and 12,
(EQ 10-37)
Note that (the elimination rate constant) is not the same as (the terminal
hybrid rate constant).
2.5 Bioavailability
Find using trapezoidal rule and, if necessary, the calculation for the ter-
minal area.
(EQ 10-38)
This is a model-independent equation.
Cl k
10
V
1
=
V
k
10
-------V
1
=
k
10

AUC ( )
0
AUC ( )
o
AUC ( )
o
t
C
p
------ + =
2.6 Dosage Regimens
The maintenance dose (D) is given by the same model-independent equation as
before,

Where has its same previous definition.
The loading dose achieves a steady-state condition quite rapidly, but only
after initial distribution has been completed. It is given by the previous equation.
(EQ 10-39)
As may be expected, equations relating and to are as
before,
Note (reference only)
All dosage regimen equations strictly apply only when,
D C
p
( )
ss
Cl =
C
p
( )
ss
D
L
( )
D
L
D
1 e
0.693N
--------------------------- =
C
max
( )
ss
C
min
( )
ss
C
p
( )ss

For digoxin Eq. 17 has a value of 0.947
For warfarin Eq. 17 has a value of 0.990
For cephalexin Eq. 17 has a value of 0.846
This is why, despite the fact that an open two-compartment model is better descrip-
tion of the pharmacokinetic of these drugs, a simple open-compartment model may
often be assumed for dosage regimen purposes.
3. Intravenous Bolus Administration: Compartment Two
It is not normally possible to measure drug concentrations in compartment two.
However, the mass of drug can be predicted based on the ddrug concentrations
observed in compartment one.
2.6 Dosage Regimens
(EQ 10-40)
Where
k
10
------- 1
k
12
k
21
------- +

' ;

1 =
X
2
B
2
e
t
e
t
( ) =
B
2
k
12
D
( )
----------------- =
Note that the equations forms bears a similarity to that seen for plasma concentra-
tions after oral administration inot a one compartment open model.
When t is large, < . Hence, Eq. 18 becomes,
(EQ 10-41)
This is comparted to the mass modification of Eq. 7,
(EQ 10-42)
Thus, when t is large the masses of drug in each compartment decline exponen-
tially, and in parallel, with time. This indicates that initial distribution has been
completed and equilibrium attained.
If the value of reflects drug concentrations at the active site, the time of maxi-
mum concentration (and maximum pharmacological effect) is:
(EQ 10-43)
4. Others Dosage Forms
The equations become complex and it is therefore difficult to obtain useful param-
eter values without th eaid of a computer. Fortunately, because the complexity of
the equations is greater than the experimental accuracy of the assays warrants,
drugs that strictly require a mammillary model can be described adequately by an
open one compartment for the purposes of calculating dosage regimens.
4.1 Intravenous Infusion
The plasma concentrations at first rise faster than an open one compartment model
profile would suggest. Later, the rise is slower. The decline, following the cessa-
tion of infusion, is biexponential.
4.2 Oral Administration
e
t
e
t
X
2
B
2
e
t
=
X
1
V
1
B
1
e
t
=
X
2
t
max
( ) ln

--------------------- =
At a time just after the plasma concentration may exhibit a nose, when
compared to the profile of an open one-compartment model.
SELECTED REFERENCES
Riegelman, S., Loo, J.C.K., and Rowland, M., Shortcomings in pharmacokinetic
analysis by conceiving the body to exhibit properties of a single campartment, J.
Pharm . Sci., 57, 117-123 (1968).
Riegelmen, S., Loo, J.C.k., and Rowland, M., Concept of a volume of distribution
and possible errors in evaluation of this parameter, J. Pharm. Sci., 57, 128-133
(l968).
Benet, L.Z. and Ronfeld, R.A., Volume terms in pharnacokinetics, J. Pharm. Sci.,
58, 639-641 (l969).
Gibaldi, M Nagashima, R., ant Levy, G., Relationship between drug concentra-
tions in plasma or serum and amount of drug in the body, J. Pharm. Sci., 58, 193-
197 (1969).
Metzler, C.M Usefulness of the two-compartent open model in pharmacokinetics,
J. Amer. Stat. Assn., 66, 49-54 (1971).
t
max
Gibaldi, M. and Perrier, D., Drug eliminatin and apparent volume of distribution in
multicompartment systems, J. Pharm. Sci., 61, 952-954 (1972).
Gillette, J.R., The importance of tissue distribution in pharmacokinetics, J. Phar-
macokinetics. Biopharm., 1, 497-520 (1973).
DRUG DISPOSITION: VOLUME TERMS
As apparent volumes of distribution are proportionality constants, and not physio-
logical volumes, more than one term is of value.
1. Apparent Volume of Sampled Compartment
This relates the concentration of drug in the sampled compartment with the mass
of drug present in that compartment.
It may be measured after an intravenous bolus dose:
(EQ 10-44)
or (EQ 10-45)
It may be measured after an intravenous infusion by:
(EQ 10-46)
V
1
( )
V
1
D
C
p
( )
o
------------- =
V
1
D
K AUC ( )
o
--------------------------- =
V
1
X
1
( )
ss
C
p
( )
ss
---------------
Q
K C
p
( )
ss
------------------- = =
2. Apparent Volume at Pseudo-Distribution Equilibrium
This volume term (sometimes known as the apparent volume of distribution of the
drug in the body) requires the assumption that the drug is evenly distributed
throughout the body. The assumption is not true in practice. Thus can only be
defined in relation to the terminal phase ( -phase) when equilibrium has been
attained; the equation is analogous to Eq. 2.
(EQ 10-47)
3. Relationships Between Apparent Volumes
By secondary alebraic definition, a clearance (Cl) is always given by the first-order
rate constant for removal of drug from the body multiplied by the apparent volume
of distribution on the drug in the compartment from which the drug leaves the
body:
(EQ 10-48)
(EQ 10-49)
(EQ 10-50)
However, systemic clearance is measured by
(EQ 10-51)
Comparing Eqs. 4 and 8, and rearranging,
V
( )
V
D
AUC ( )
o
--------------------------- =
Cl
r
k
u
V
1
=
Cl
m
k
m
V
1
=
Cl
s
KV
1
=
Cl
s
D
AUC ( )
o
----------------------- =
(EQ 10-52)
Comparing Eqs. 7 and 9,
(EQ 10-53)
Selected References
Riegelman, S., Loo, J.C.K., and Rowland, M., Concept of a volume of distribution
and possible errors in evaluation of this parameter, J. Pharm. Sci., 57, 128-133
(1968).
Benet, L.Z. and Ronfeld, R.A., Volume terms in pharmacokinetics, J. Pharm. Sci.,
58, 639-641 (1969).
Gibaldi, M., Nagashima, R., and Levy, G., Relationship between drug concentra-
tions in plasma or serum and amount of drug in the body, J. Pharm. Sci., 58, 193-
197 (1969).
Perrier, D. and Gibaldi, M., Relationship between plasma or serum drug concentra-
tion and amount of drug in the body at steady state upon multiple dosing, J. Phar-
macokin. Biopharm., 1, 17-22 (1973).
Oie, S. and Tozer, T.N., Effect of altered plasma protein binding on apparent vol-
ume of distribution, J. Pharm. Sci., 68, 1203-1205 (19793).
Li;vxrX LLrLLxLS
Cl
s
V
=
V
----V
1
=
Drug is usuallo sampled from the centr->l compartment, designated compartment
one.
1. Laplace Transforn for Compartment One
As,l
(in)(dS 1)
where As,l is Laplace Transform for mass of drug in comPartment one
s is the Laplace Operator in is the input function
dS,l is ehe disposition function for compartment one
2 InDut Functions
. .
N ehat input need not necessarily be to compartment one.
2.1 IV Bolus
(in) - D
where D is the dose
2.2 IV Infusion
Q (l-e sb)
where Q is the zero-order infusion rate, b-t when e<T, b-T when eiT, and T is the
eime of cessation of infusion.
2-3 First-order Absorption
(in) . <
(s+ka)
where ka is first-order absorption rate constant, ant F is the fraction of D ultimately
reaching the general circulation.
2-4 Dissolution and Absorpcion (type 1)
(in) - krkaFD
(s+kr) (s+ka)
where kr is tirst-order dissolution rate constant.
2 5 Dissolution and Absorption (tvpe 2)
(la)
ka(l-e sb)
s(s+k>)
where ko is zero-order dissolution rate, ceasing at time T.
2-6 Others
These may be formed by adtition of functions 2-1 through 2-5
e.g., (in) - D + Q(l-e~Sb)
This denotes the simultaneous commencement of an I.V. bolus and infusion.
3. Disposition Function for Comcartment One
A driving force compartment has one or more exit rate constanes; for
.
instance, in compartment i, ehe sum of ehe first-order exit rate constants
is Ei.
As,~
n~
kca a +
where q is the compartment into which input occurs, n is the number of driving
force compartments,
i,j, and m are counters (maximum value of n),
kql is the first-order rate constant for transfer of drug from input compartment eo
compartment one,
kl; and kjl are the first-order rate constants for drug transfer from compartment 1 to
compartment j, ant vice-versa.
3-1 Using the disposition function
(a) If q-l, ehen kqlsl
(b) Tr (Pi) and fT (Pm) are coneinued produces. ~e value of Pi (or Pm) equals one
when thc counter i (or m) takes on a forbidden number. For example, i-l is forbid-
den in the numerator, ant m-l and m-j are forbidden in the denominaeor. 3-Z
E.camples
(a) one-compartmene open model (n-l,q=l)
ds,l = 1 (Eq.l)
(b) Two-compart:.ent open models (n-2.q=1)
(s+E~)
ds , 1
(s+El) (s+E2) - kl2kx
(c) Three-compartmene open models(n-3,q-2)
dS,l
k21 (s+E3)
(Eq.2)
(s+El) (s+E2) (s+E3) - kl2k21 (s+E3) - kl3t31 (5tk2)
(Eq.3)
3-3 Simplifying the Denominator The number of exponeneial terms in ehe final
ineegrated equation will be equal eo the number of driving force compartments
(n). This is also equal to the maximum power to which the Laplace operator (s)
would nppear if
the denominator were multiplied out. Hence, the denominator is simplified n to
become iXl (S+ki), where ki is a composite first-order rate constane.
(a) ds,l
(b) d5 l
(c) ts.l
(s+kl)
(s+E2)
(s+kl) ts I k2)
k21 (s+E3)
( s+kl ) ( s+k2 ) ( s+k3 )
(Eq.la)
(Eq.2a)
(Eq.3a)
The exact meaning of [i for any model depends on the equalities evident in the
denominaeors. Example for (b):
(s+kl) (s+k2) - (s+El) (s+E2) - kl2k
4. Method of Partial Fractions Ihis method is used to solve (integrate) a Laplace
Iransform providing there are no repeating factors in the denominator. Example:
no 52 or (s+ki)2
l 1 Prepare che Laplace Transform
Example: I.V. bolus into compartment one of two compartment model
( s+kl ) ( S+k2 )
4-2 Obtaining the Roots of Denominator Factors
If the factor is s, the rooc is zero
If ehe faceor is (s+ki), the root is
4-3 Ridden-Hand Method
(a) Deal with each factor of ehe tenominator in turn.
(b) Cover the factor with a finger, and remember its root.
(c) Wherever the Laplace operator(s) occurs in the uncovered transform, subseitute
the root for s.
(d) Multiply the resule by eses again substituting ehe rooe for s
(e) After doing (b) through (d) for each factor, simplify.
Example:
X1 D(-kl+E2)e-klt - + D(-k2+E2)e~k2t
(-kl+k2)(-k7+kl )
or C1 - D (kl-Ez)e kl + D (E2-k2)e 2
V1 (kl k2 )
or C1 - Ale 1 + A2e-k2t
In this example the meaning of A1, A2, kl, k2, and E2 depend on the form
of the two-compartmental model.
5. Laplace Transform for Peripheral Compartments
This is obtained by the following procedure, which is analogous eo that
employed when using the Laplace Transform table.
(a) Write the differential rate equation.
(b) Take the Laplace Transform of each side of the differential rate equation, using
the table where necessary.
V1 (kl-k2)
(c) Algebraically manipulate the transformed equation until an equation having
onlv one transformed dependent variable on the left-hand side is obtained.
(t) Substitute for anv known transformed dependent variables on tlle right-lland
sidc of the equation.
(e) Solve (integrate) bv the method of partial fractions (tlle hidden 1land), and
simplifv.
6. btethod if Denominator Contains the Factor 52 This may apply to terminal
compartments, such as urine, following an I.V. infusion. The hidden hand
method cannot be used for the factor 52 in the denominator as it has no simple
root.
6-1 Example (n=2, q^l, exit from compartmenr one):
aS,U - kloQ.(l-e~sb)(s+Es)
52(5+kl) (s+k2)
where klo is the first-order excretion rate constant from compartment one.
xu ~ kloQ.E2b + ......
klk2
where Xu is the cumulative mass of drug excreted into the urine.
The other factors can be used as before in the hidden-hand method.
6-2 Example (n-3, q-l, exit from compartment one)
aS u kloQ.(l-e 5b)(S+E2)ts+E3)
s2(s+kl)(s+kv)(s+k3)
Xu t kloQ- E2Elb I
klk2k3
REFERENCES
L.Z. Benet, General treatment of linear mammillary models with elimination from
any compartment as used in pharmacokinetics, J. Pharm. Sci., 61, 536-541 (1972)
D.P. Vaughan, D.J.H. Mallard, A. Trainor, and M. Mitchard, General pharmacoki-
netic equations for linear mammillary models with trug absorption into peripheral
compartments, Europ. J. Clin. Pharmacol., 8, 141-148 (1975).
D.P. Vaughan and A. Trainor, Derivation of general equations for linear mammill-
ary models when ehe drug is administered by different routes, J. Pharmacokin.
Biopharm., 3, 203-218 (1975).
Two-Compartment Model-l
Prior inputs focuset on one-compartmcnt models, but many drugs arc charactetizet
bettcr by multicompartmcnt motek. In the following three inputs, we shall bricfly
tiscuss multico~_nt motek ant prcstnt a few apB plicadons. Multicompartnent mot-
cis are not uset as fo quentlg u the one-compartment model in therapeutic trug
monitonng, panly because they arc more tifficult to construct ant apply.
Gencially, muldeaw models arc appliet when th,e natural log of plasma drug con-
sentration vcrsus time is not lincar afier an intravenous tose or when thc plasma
concentration versus time psfilc cannot bc chu~ by a single cxpooential function
(i.c., C, - CO e~~). Wben the In of plasma concentration vcrsus timc is not a
stnight line, a multicompartmcnt model must bc constructet to tescribe the change
in concentrations over time.
Of the mul
models, tbe two-compartment motel is tnost fxqucntly uset. lunis model usually
of thc weU-perfia
tissues ant penpbexal compartment of less weU Erfuset dssues (such as muscle
ant fat). hgure 23^ shows a diagram of thc two-compartmcnt model afir an intrave-
nous bolus tose, where:
consists of a central
Xfamount of diug in centnl comva XP s amount of drug in psipheral cowt
K,2rate const nt for transfcr of drug from cd-compartment zo petipheral com-
partment rne subsaipt 12 irldicses tr nsfcr from thc first (cd) to the second
(peripheral) compattments.
K2, - rate constant for tgansfcr of drugfrov peripheral computment to central comp
rtment lbe subscript 21 indicales tr nsfcr from Ulc second (periphaal) to the fint
Xo~
Kl2
K2l
+ Klo
zgre23~ Gr phic reprtsentation of a zwbcompattment model.
(centri) compartments. (Nott h Kz2 and K2,calkd micxnts.)
fintvder climinX aue consunt (similar to tbe Jr uxd paviously), iting elimiXn of
dmg out of tbe caul ~ into urine, feces,
esc~
A log plasma conscatration versus time curve for a two-compattment model shows
a curvilinear profilea atrved potoon followed by a straight li=. This biexponen-
tial curve c n bc described by two expoKntial tcrms (Flgure 23B). lEc phases of
the curve may reprcstnt rapid d1stributioo to organs with high blood flow (central
compuenent) and slower distnbution to organs with Ess blood flow (penphcnl
compartmcnt).
Mer thc intovenous injection of a drug that follows a t_ model, thc drug consentra-
tions in all fluids and dmms associated with tbc central compartmcnt declinc morc
rapidly in tbc distributioo phasc thao during the post-diwibubon phasc. ARcr sornc
tirnc, a pseudocquihEutn is attained betwcen thc ccotral compartmcot and thc
dssucs atid fluids of toc pc ipheral compO thc pl sma coocentration vcrsus timc
ptnfile is thco chaserized by a linear pnmcess.
For many drugs, suco as aminoglycosides, thc distributdoo phast is vcry shott (e.g.,
1920 mtn). If serum consentradons are measured after this phase is compited, toe
ceotral compartmcot can be ignorcd and a one-compartrKnt model adequatcly
repttsents the serum coocentratioos observed. However, for drugs such as vanco-
mycin, thc-distribution phase lasts 1-2 hr after an intravenous dosc. If plasma con-
centrations of vancomycin are determined within the first hour after a dose is
given, thc nonlincar (multiexponential) decline of vancomycin concentrations
must bc considered.
REVIEW PROBLEMS
23.1. In the twocompartment model. Xt wpresents the
23.2. The log plasms concentration vcrsus time curve for a two-compartment
model is reprcsented by a (bicxponential or monoexponential) cuNe. (Sclect one.)
23.3. The first portion of the log plasma concentration ver. sus timc cune. where
the log concentration r;tpidly declincs. is lomwn as the
phasc.
23.4. The final. Iinear portion of the curve is the phase.
11- 1
~1
I>Pur 2t 61
70 [ So
~i
~m
~ .
F*wf 238 Four st ges of drug distribution nd eliminatioo following rapid intrave-
nous injectiott. Points I, U, m, nd tv (ript) corrcspond to the points oo the plasmx
concentntion curve (leR). Point 1: The injection has just becn compicted, and drug
density io the cd compartment is hipcst. Drug distribution and elimination hve just
begun. Poin~ 11: At midway through tbe distributioo process, the drug density in
thc central compartment is falling r pidly, dulioly owing to rapid drug distributioo
out of the centd ccrnpartment into the peripheral compartment. The density of drug
io the peripheral compartment has not yet mched tht in the central compartmcnt.
Poixt 111: Distribution equilibrium h s been attained, and drug densitics in the
centd and periphed compartments arc appgoximately equal. Drug distribution in
both directioos contioucs to talze place, but the ratio of drug quantitics in toe centel
and peripheral compartments remains constant. At this point, the major determi-
nant of drug disappearance from thc central compartmcnt becomes the elimination
process; previously, drug disappearance W&S determined mainly by distribution.
Poi/s : During this elimination phase, the drug is being -drained from both com-
partmcnts out of the body (via the central companment) at approximatcly the same
rate. (Reproduced, with permission, from Grecnblatt DJ &nd Shader Rl, Phrma-
colsinetics in clinical practice, W.B. Saunders, Philadelphia. PA, 198S.)
TwoW M~
lo this input, wc soall apply mathematicaS principles to toe two-compartmcnt
model to calculatc useful poarmacokinetic parameters.
horo tiscussioo of the ooe-comparaneot model, we koow that the climination zte
coostant (J[) is estsmated fxm the slope of the lo pbsma coocentration vcrsus ame
curve. However, in a two-canzrg tnodel, wose the lo plasma coocentration versus
time curve is curvilinear, the slope varics, tepcndiog on waich porioo of toe curve
is cxamined (Flgurc 24A).
In a two compartment model, the tenninal slope from the pos,t-digributive phase of
the curve may bc backextrapolata~ to axnc zero (T). The oegative slope of this line
is teferret-to as beta (O, aot ,B is the tennioal eliminatton tate coostant of the trug.
The iotesept of this lioe on the In plasn coocentration axis is koown as B and is
uset in vanous two~cotnpeneot equations.
Bc~ is similtr to K in to t it vsents the tsminal elim meion r te constant. From it, a
half-life can be cal~ culS
T%, 0.693
is
which is refenet to as the beta haSf-Ute.
lEroughout the ame th_t trug is present in the boty, tistribuiion takes place between
the central ant peripheral compartmenu. We can calculate a ratc of tistribuaion
using the mct rcsidxals. This methot estim tes the cffect of distribution on the
ovcrall plasma concentration curvc and uses thc diZfcrcncc between thc cffect of
climination and thc actual plasma consentrations to determinc thc distribution rate.
In the In concentration versus vime curvc in Flgure 24A, the slope of the initial
portion is determined prim--arily by the distribution rate while thc tenninal portion
is determined primarily by thc climination rate.
E <~
100
50
o
S~
PodwDiattibutlon
Ph~
Timo Figsot 24A Plasma druy concentralions with a two-compartment model atter
an imravenous bolus do*c.
The methot of residuals may be used for calculating phamiacoMinctic parameters
of thc two-compartmcnt model. FuSst, b cl:-extrapolate the terminal straight-line
portion of tbe curve (Flgure 24B). If w, s. y, and 2 are actual, detennined concen-
tration time points, let w, ~, y, and 2 xpresent points on the new (extopolated)
line at the same times that tbe aaual points were obscrved. These newly generated
points xpresent the cffect of clim~ ination alone, as if distribution had been instan-
taneous. Subtnction of the extrapolated points from the corresponding actual
points (ww, X~, etc.) yields a new set of pbsma concenti-ation points for
each time point. If we plot tbese new points with the appmpriate times, we gener-
ate a new line, the residual line (hgure 24C).
The slope of tbe xsidual line isst, and alpha (a) is the distribution rate constant
for the two-compartment system. The intrcept of the residual line is A. Therefore,
witb the coocept of residuals, we attempt to separate the two pwocsscs of diseribu-
tion and climin~ jon.
Ist us now pn~cood through an exampic, applying thc metbot of xsidtis. Draw tbc
plot for thc following cxampb on somilog gnph paper. A dosc of dnag is ad
10.0
50
:!
Z c 10
o
fL Q
Tlmo F~241R Mcthod of xsiduals.
E
100
5e
Y
Bz
~
\ Sbpo = a
s -R
Timo
F; 24C Dctermination of the rcsidual linc.
62
InPtJT 24 63
)
ministered by rapid intravenous injection, and the tollowing concentrations result:
Tkne afttr
Dose (hr)
0.2S
O.S
1.0
I.S
2.0
4.0
8.0
12.0
16 0
Plasms
Concentration
(u~/ml)
43
32
20
14
11
6.S
2.8
1.2
0.S2
A linc is trawn connecting the last four points and intcnecting the y-axis. Then, for
the first five points, cxtrapolated values can be cstimated at cach time (0.2S, O.S,
1.0,l.S, and 2.0 hr). If the extrapolated values from the actual plasma concentra-
tions are subtracted, a new set of points is generated (resitual concentration points)
as fts w~
Tlnse dir
Doz (hr)
0.2S
O.S
1.0
1.5
20
Pbsma Concentratlon (>g/ml)
^>e
Exupol ted Residud
14.S 28.S
13.S 18.S
12.3 7.7
1 1.0 3.0
!O.0 I.D
The zsidual concentrations are then plotted (on semilog paper) versus time, and the
slope of that plot equals 1.8 hr~t. When the negative is dropped, this slope
equals sx; we observe from the plot that the intercept (A) of the line is 4S Fg/ml.
We also can estimate a from the slope of the terminal straight-line portion (equal to
0.21 hr~ ~) and 8 (equal to IS 1lg/ml).
Alpha (ex) must be greater than beta (a), indicating that drug removal from plasma
by distribution into tissues proceeds at a greater rate than does drug removal from
plasma by eliminating organs (e.g., kidncys and liver). rhc initial portion of the
plot is steeper than the terminal portion.
REVIEW PR08LEMS
24.1. Dnw a log pbsma concentntion versus timc profile for a drug Oinimed by the
intravenous bolus nmute and best durizZ by a two-companrnent modeJ (Figure
24D).
242. Tbe slope of the tenninal phase of the above. plot equals
243. Tbe inucept of thc tenniial portion on tbe In pbsma concentstion axis is tenned
>.~ sca(g)~ tbe tenninal const nt of the dmg s it leaves the body.
24.S. One w y to calculatc a distnbution zate is to use tbe metbod of
24.C. Tbe fint step in the metaod of residuals is to.
- the telminal straight-line portioa of the curve. 24.7. The extryolatd points aw
subtmed from tbe actuaJ observed at the correspoading times.
24.8. Tbe slope of the residual line equals
24.9. A is tbeof tbe In
plasnu concenamtion axis by tbe
line.
2410. Tbe coocept of residuals attempts to separate tbe two
processes ofand
100
50
ca e
Z c 10
F Q
Fkwe 24D
Tim
l j g
Two-Compartment Model-3
The estimations of A, 8, ss, ant t perforrned in tbe last input are useful for predic-
ing plasrrs concentotions of dmg ch~nzi by a two-compartrnent model. For
awrst rnodel (Flgureo2SA), we know th t thc plaSsma concentration (C) t any
time (t) can be dessnbet by
Cf ^ Ce e t
where CO is the initial concentration and g is ttne climination rate. Thae two-com-
partment rnodel (Flgure 2SB) is thc surn of two linear components, reprcsenting
distnbution ant elimination (Flgurc 2SC).
In thc sarnc w y, we can dctrminc dnag consentration (C) at ny tinx (t) by iding thc
two linear components. In cach casc, A or B i-s uset for CO, ant ex or z is used for
XY. Therefe
C, s +- 8 e~*
ThiSs equation is called a biexponential cquation bccausc two cxponents rc
iwaled. With thc onos
wrunt rnodcl (intravenous), wherc:
C. s Ce e ~
2 B
100
501
CO
10
S
Timo Fzwe 25A Pls dmg concentrations with a one com putment model aher an
insvenous bolus dose (first order elimination).
100
50
, o
z -, 10
5
~ c
o
Timc ft 25B Plasma drug concentrations with 3 two compartment model after an
intnvenous boluXs dose sfirst-order elimination) .
100
50
E; tO
Sz
Tlmo
Fw 25C lOr azmpo~s of a twozxpo~ (>
t) model.
~nentid becausc thc linc is
t tnodel, diffcrcnt volume of
thc equation is
describet by onc exponents
E or thc twowrat dWibution psramctrs cxist thc centol volurnc {V), thc cxtrapo-
lated volunc (V,~ ,), tbc volunc by arca (V,,, also lcnown as V~|), ant thc stcadys-
tatc vohunc of diwibuX (V,,). Each of thcsc voluncs rclste to diffcrcat undertying
assumptioos.
As in thc onc-cornpenent rnotcl, a volunc can bc calculated by
V dose dox
,~ + B Co
For thc two-compartrnent model, this volurne would bc cquivalent to thc volumc
of the central compartment (V). Thc Ve rclates the amount of drug in thc-central
compartmcnt to the concentration in the central compartment. In thc two-compar-
trnent model, CO is determined by cxtrapolating back to thc y-axis from the upper
or initial straight-line portioo of the plot.
When we calculate the extrapolated volume of distribution (V,x,,,p), we assume
that instantaneous distribution has occurred. The effect of the iniial distribubon
phase is ignored:
da
B
V_
wherc B is the w-intetcept of thc line extrapolated from the terminal portion of the
curve. This volume of distribution determination may not provide a useful volume
term since it ovcrsimplifics the two-compartmcnt model and disregards thc distri-
bution phasc.
Another volumc (V,,O or V~) is detcrmined from the area under the plasma con-
centration vcrsus time curvc and thc tcrminal climination rate constant. This vol-
umc is related as follows:
114
lNvts S 65
vffi
dox CL
=
ffi x AUC3
va
This calculation is not subject to thc ovcrsimplification of V,S,,p, but it is affected
by changes in clearance. The V,,,, relates the amount of drug in the body to the
concentration of drug in plasrna in the post-absorpion and postwdisttibuiion phase.
A ffnal volume tenn is the volume of disttibution at steady state (V,,). Although it
is not affected by changes in drug eliminadoo or ckarance, it is more difficult to
calculate. One way to estimate Vs, is to use the two compartment microconstants:
V,Ve + ~2vf
21
or it may be estimated by more complicated methods using AUC.
Since-different methods can be used to calculate the various volumes of distribu-
tion of a two-compartment model, you should always specify the metbod used.
When reading a pharrnacolcinetic study, pay particular attenion to the method for
calculating thc volume of distribution.
REVIEW PROBLEMS
2S.1. The terminal eliniination rate constant tn a twoaconF putment model is
2S.2. For the two-compurtment model. complete the equo tion describing the
relazionship of plasma concentration with time: C, -
25.3. (True or False) The equation describing elimination afer an intravenous bolus
dose of a drug charauerized by a two-compartment model lequires two exponential
terms.
2!;.4. A patient is given a 500-mg dose of drug by intravenous injection and the
following plasma concentrations result:
Plssms
Time snerConcentrstion
Dese (hr)ItsSml)
Oo ss
0.7S
l S
3
,6
72.0
46.0
33.0
26.3
20.0
16.6
1r.2
9.0
5.0
_.7
n Rr
Plot the points on semilog paper Ithree cycle) and deterTnine the following: a. ~. b.
B. c. Residual concentrations for the first five points. d. A.
. t.
Prodictod Dlssma concentration at 1.2 hr after the
dose.
S- V,.
h. V,, (if AUC = 131.S mg/L x hr and dose SOO mg).
~ A#=W{~ SGS 2
PRi4CTlCE SET 2
The following pxbiems are for your xview. Dcfinitions of symbols ant Icey equa-
tions = pxvitet hc~:
k ~w climinton nte cowt
C, s pbSllk tn~ _jUSt Aher a single inuvenous injectioQ
e - bese for the nxl log f~|eion - 2@71S
4 - nte of tose ~ion (msy be cxptesset as
milligsams per bour in the sense of a coQtinuous
infusion or u trug tose divitot by itifusion tune
for intemtittent infusions)
V voluxne of tistribution
C_t - pcalc p1ssfu a ocentntis
C_ tnmugn plsCOOCCD
a steaty state
a stcady st te t duFn of intsvenous inAlsion
For muldpk dose, intennittent, intnvenous bolus injeciiOQ g stF st~
k V (I - e~t)
C_Cw e~t
For muletplffbse~ intctmiu, intnvenow itafi~ioo
C - t (I ~ e t~)
~ VK (Ie~tD
C_ - Cp e~tt~4
Fot contitiuous infusion before stee st te is reacbed:
C - V^r (I - C-t)
For continuous infusion t stcaty stac
C.4. 4
Vt Ws
PS2*1. A 60-kg patient is begun on a continuous intravenous infusion of theophyl-
line at 40 mgtbr. a Forty-eight hours after beginning ttte infusion, the plasma con-
centniion is 12 ~/ml (12 mg/L). If we assume that tbis COncentRtiOD is tbe stcady
state, wb t is the tbeoobylline clearansc?
b. If the volume of distribution is cstimated to be 30 L, what are the X and half-
life?
c. Since we kww V and t. what would the concentntion bc 10 hr aftcr beginning the
infusion?
d. ff the idision i continuet for 3 days ant then discondauet, what woult tD plamS
consentm tion be 12 hr ~r stopping the infwiont
e. If tne infusion is continuct for 3 d ys at 40 mg/ hr ant the stcaty-statc pluma con-
centtation is 12 Fg/tnl, WDat rate of trug infusion would liltely xsult sn a concen-
tradon of 18 ~/ml?
f. ARcr the iocosed infusion nte above is begun, how bog would it tic to tuch a plu
coo~ cenudon of 18 Fgiml?
PS2< A 60-log p ekat is st rted on 80 mS of gentunicin ewety 6 br in I*br infu-
siagL
L If this pSt is us led to have an avenge V of 15 L ult a normal half-life of 3 hr,
wtuat will be the pealc plm cocenttadon at stcady stuc?
b. After thc fifth tese. a peak plasma concentratlon (dsawn at thc ent of thc infu-
sion) is S Ag/ml ant thc ttnugh consentration (drawn right befott thc sixth tosc) is
0.9 Ag/ml. What is thc patients xtual gentamicin half-life? What is thc xtual vol-
ume of disvribution?
c. For this patient, what dosc should bc administen:d to reach a new steady-state
peak gentamicin concentration of 8 Fgiml? At this dosc. what will bc thc steady-
state trouQh concentration!
II_q
tFoD~ sU
~ Tvo-ConPart-ent Open Hodel
tatlente ufferln~ chronle tenal fellure often require h _ odiolyele. Drug~ cy be
~dxinletered by Injeetlon Into the wenoue lde of the he odtcl~ser ~chine
Such e rituetlon vax ~ecerlbed by L tourneeu-Scheb t 1 (Int. J. Clln. tharv col IS
116-120 {1972)) for lx pctlente vho received n introvenoue done ot gent _ letn
(90 ng). The neen etru- concentrctleno et sent~nicin (C~) hovvd blexponenttel
deellne vith tl t (t).
Ce t
(-~lllter)(oln)
o 60 10
5 75 20
5 25 lO
4 80 40
50 50
3 95 90
3 40 150
3 10 180
2 90 240
2 55 28S
(
o. Caleelete the ter lnal half-llfe (t~) the hybrid rete eonetento
nd O nd the coefflelente (~1 3 Sl) for gent- leln to theeo he-odlulyal~ putlente
b. tor ubJecte vith noreel renal functlon. the yete-le elearence (Cl~) of gentanletn
le pproalaetel1 0.041 llter/ In. Sec uee 98X ef Cl~ le due to excretlon of
unchanged drug. renel tciluro utll ~rkedly effect ~ent~lcin clecr~nce.
Show vhether the petlent~ undergoinfS he odlelyele xhlbit o nor-ol gentcnicln
yett-le elexr~nce.
Calculete the two pperent volune ot dletrtbut10n terwe (V nd V )
nd the ell fnetlon rete eonetont. Uhet frectton of tho gt ted eln ln the body fter 3
hr nlght be la the peripherel ee part~ent7 At vh t tbae doee the gent _ Icin in the
peripherel ee pert~ent rench
~t
4. Under the eondittons of h odSxlyxte. coleulete the doxe tD) of
sentcoleln tlSch vould be dolaletered very S hr {1) In order to ~alnteln n
everogew teady-ctete erus concentretlon of 4 g/llter.
. Wlthout the hc odielyrer two ~ale petlente ach xhlbited creetinine eleorence
(Cle ) of 5 llwin; the norx~l velue le 117 t 20 I/nin. A~using that the deereFeed
Clcr {e due to decresce In glo-eruler filtretloo rcte vhst vould h-ve beeD the renel
clecrxnce (Clr) of gent~elcia In there two patlentn hed they rz cined vithout the he-
odlolysert Uhct done vould then need to be dsinletered every hr to n Intoin (C~ t
4 tert Co pcro your eouer wStb tho thy~telea e Deek Refer neo.
Vancomycin is an antibiotic used in the treatment of endocarditis in patients aller-
gic to penicillin. It is poorly absorbed orally and acute pain is associated with inter-
muscular injection. I.V. is the route of choice. After a 1 gm I.V. dose the following
data is observed:
.5 51
1.0 36
1.5 28
2.0 23
3.0 18.5
4 o 16
6.0 12.5
8.0 9 9
12.0 6.25
FIND: a) A1 ;
b) alpha
c) Clearance ;
d) * of drug in peripheral compartment at equilibrium .
Clearance:
In normals, Erythromycin is cleared 90% by metabolism and 10% by the kidney.
Also, it is 90% protein bound at therapeutic levels. Welling and Creig (JPS 67,
1057-9,1978) reported an increase in the half life from 2.0 to 2.3 hours while also
reporting an increase in clearance from 275 to 485 ml/min and an increase in Vdss
from 57 to 100 litres when comparing normals to uremic patients. (Uremic patients
suffer from inveased concentration of urea as a result of severe renal failure.) A
physician has just called you and asked you to explain how he could have seen an
increase of 15% in the half life and a 75% increase in clearance at the same time
and what is the impact of this on antibiotic therapy for his uremic patient. In clear
concise English (not techno-bable), prepare a short written answer to this request.
Keep in mind that the man who requested the information is a medical professionat
intelligent, and very busy.
The following data was collected from a normal patient in the revious study (Well-
ing, op. cit.) following an IV bolus injection of 500 mg of erythromycin (as lacto-
bionate salt ).
time (hr)concentration (mcg/ml)timeconcentration
0 12 4 3 2.6
1 6.4 4 1.9
2 4.0 6 1.2
8 0.4
~ .
Fmd the peak time in the peripheral compartment.the fraction of the drug in the
peripheral compartment at four hours.
Two compartment model
Spectinomycin (TROBICIN^TR^T) is an aminocyclitol antibiotic shown to be
active against most strains of NEISSERIA GONORRHOEAE at a minimum
inhibitory concentration of 20 mcg/ml. The usual adult dose is 2 g (4 g in areas of
known resistance) given I.M. through a 20 gauge needle. Initial studies were done
by the company to determine the pharmacokinetic parameters of the drug. The data
from a single IV Bolus dose of 0.5 g is as follows.
Time (minutes)Concentration
10 63
20 51
30 43
45 35
60 30
120 183
240 7.6
360 3.2
FIND:
(5 points) a) A^V1^V =
(5 points) b) B^V1^V =
(5 points) c) Clearance =
(5 points) d) t max in the peripheral compartment =
(10 points) e) % of drug in peripheral compartment at equilibrium =
Spectinomycin (TROBICINR) is an aminocyclitol antibiotic shown to be active
against most strains of NEISSERIA GONORRHOEAE at a minimum inhibitory
concentration of 20 mcg/ml. The usual adult dose is 2 g (4 g in areas of known
resistance) given I.M. through a 20 gauge needle. Initial studies were done by the
company to determine the pharmacokinetic parameters of the drug. The data from
a single IV Bolus
dose of 0.5 g is as follows.
Time (minutes)Concentration
10 63
20 51
30 43
45 35
60 30
120 18.3
240 7.6
360 3.2
b} B c) Ciearance d) t max in the peripheral compartment e) % of drug in periph-
eral compartment at equilibrium
The following information is offered from a 142 mg IV bolus dose of grisiofulvin
given to a 73 Kg man.
Time mcg/ml
1 1.67
2 1.22
3 .97
4 .83
6 .66
8 .56
12 .42
18 .27
24 .17
30 .11
Find A1, B1, alpha, beta, K10, K12, K21, Peak time in the peripheral
compartment, % in the peripheral compartment at equilibrium.
Can you assume that this drug can be estimated by a one compartment
model upon multiple dosing ?
Quinidine is current-ly used to treat ventricular and supraventricular arrythmias.- It
is available as a sulfate, gluconate, and polygalactouronate which contain 83%,
62* and 60* by weight free base (pRa 8.6). Qunidino sulfate is available in 200,
260, 300 and 325 mg tablets, while quinidine gluconate is available in 325 mg tab-
lets. The following pharnacokinetic parameters are reported by Ueda:
PARAMETER
C1 renal (ml/min/kg)
C1 hepatic (ml/min/kg) V1 (L/kg)
V beta (L/kg) F (oral)
t 1/2 alpha (min) t 1/2 beta (hr)
MTC (mic/ml) NEC (mic/ml)
Population Ave (+ SD)
0.93 (0.52)
3.26 (1.74)
0.66 (0.38)
2.61 (1.10)
0.71 (0.16)
6.69 (4.03)
6.44 (1.63)
8.53 (0.81)
* , 1.85 (0.19)
% bound to protein80.00(2.50)
During the last pharmacokinetic exam you noticed ome cardiac problems.
Wh n you ch-cked with your physician, He prescribes quinidine. What
dose should you be on?
Later, he diagnoses mononucliosis from lack of sleep and poor ating h bits s weli
as cardiac arrythmias. Your liver funcion has dropped to 60* of normal. He pre-
scribes quinidine for you. What is the dose that you should be on ?
ie. -
ll-3
Quinidine is currently used to treat ventricular and supraventricular arrythmias. It
is available as a sulfate, gluconate, and polygalactouronate which contain 83%,
62% and 60% by weight free base (pKa 8.6). Qunidine sulfate is available in 200,
260, 300 and 325 mg tablets, while quinidine gluconate is available in 325 mg tab-
lets. The following pharmacokinetic parameters are reported by Ueda:
PARAMETERPopulation Ave (+ SD)
C1 renal (ml/min/kg)0.93 (0.52)
C1 hepatic (ml/min/kg)3.26 (1.74)
V1 (L/kg)0.66 (0.38)
V beta (L/kg)2.61 (1.10)
F (oral)0.71 (0.16)
t 1/2 alpha (min)6.69 (4.03)
t 1/2 beta (hr)6.44 (1.63)
MTC (mic/ml)8.53 (0.81)
MEC (mic/ml)1.85 (0.19)
% bound to protein 80.00 (2.50)
During the last pharmacokinetic exam you noticed some cardiac problems. When
you checked with your physician, He prescribes quinidine. What dose should you
be on?
Later, he diagnoses mononucliosis from lack of sleep and poor eating habits as
well as cardiac arrythmias. Your liver funcion has dropped to 60% of normal. He
prescribes quinidine for you. What is the dose that you should be on ?
Methotrexate is a cytolytic used for the treatment of acute leukemia and other
forms of cancer. After a a 400 mg/kg dose the following data was recorded for a 12
y/o boy.
Time (hours)
6
12
18
36
48
60
72
90
Concentration (mcg/ml) 360 70 15
2
1.2
0.46
0.36
0.15
bA) B c) Clearance d) % of drug in peripheral compartment at equilibrium
PROBLEM SET
zumper w~wFS
t L) v , ~ s D fv
Patients suffering chronic renal failure often require hemodialysis. Drugs may be
administered by injection into the venous side of the hemodialyzer machine.
Such a situation was described by L*tourneau-Saheb et al (Int. J. Clin. PKinma-
col., 15, 116-120 (1977)) for six patients who receivet an intravenous dose 7 gen-
tamicin (90 mg). The mean serum concentrations of gentamicin (Cs) showed a
biexponential decline with time (t).
(~9cyml) (mRn)
6.60 10
5-75 20
5.25 30
4.80 40
4.50 50
3.95 90
3.40 150
3.10 180
2.90 240
2.55 - 285
. .
(a) Calculate the values of t1/29 B, Bj, ~, A~, and V1. LFtourneau
Saheb et al reported,
tl/2 = 5.50 t 0.77 hr (mean i SD)
B s 0.0022 t 0.0004 min 1
B1 s 4.76 f 0.62 vg/ml
v 0.053 t 0.009 min
A1 a 3.47 s 1.01 pg/ml
V1 s 11.3 ffi 2.0 litre
(b) Calculate C1 and VB
LFtourneau-Sahleb et al reported,
C1 s 40.8 t 7.8 ml/min
VB s 19.2 h 2.7 litre
_1
11-33
98X of the systemic clearance of gentamicin is composed of renal clearance-of
unchanged drug, so that renal failure woult severely alter gentamRcin systemic
clearance. In this case, the use of the hemodialyzer gave a systemic clearance close
to the 41.0 ml/min seen in patients with normal renal function.
(c) Under the conditions of hemodialysis, calculate the dose (D) of gentamicin
which would be administered every 8 hr (t) in order to maintain an Waverage
steady-state serum concentration of 4 ug/ml. What would be (Cmax)ss and
(Cmin)ss?
(d) Without the hemodialyzer two male patients each exhibited a creatinine clear-
ance (Clcr) of S ml/min; the noW l value is 117 + 20 ml/min. Assuming that the
decreased ClCr is due to a decrease in glomerular filtration rate, what would have
been the renal clearance (Clr) of gentamicin in these two patients had they
remalned without the hemodialyzer? What dose would then need to be adminis-
tered every 8 hr to maintajn (~s) at 4 ug/ml? Compare your answer with the Physi-
cians Desk Reference (5677).
Your third patient comes from Edelman et al (Clin Pbarmacol Therap 35:382-6
(1984)). He studied metotrexate is artbritic patients. The pharmacokinetic parame-
ters gleened from the 10 mg IV data arc:
A1 (mg/L) 0.663 Alpha (hr-1) 059 B1 (mg/L) 0.073 Beta (hr-1) 0.097
15) What is the AUC (0 to inf) (mg / L * hr) ?
a) 0.75 b) 1.08 c) 1.12 d) 1.88e) 9.1
16) What is V1 (L) ?
a) 13.6 b) 15.1 c) 253 d) 36.1e)103.1
17) What is the clearance (L/hr) ?
a) 53 b) 8.9 c) 133 d) 15.4e) 17.2
18) What is V(beta) (L) ?
a) 13.6 b) 253 c) 36.1 d) 45e 55
19) What is the t(max) in the perepheral compartment (hr) ? a) 0 b) 1.8 c) 3.7 d) 5.1
e)6.1
20) What percent of the drug is in the perepheral compartment at cquilibrium ? a)
25 b) 50 c) 75 d) 100 e) 125
Two compartment: It has been proposed (Ionescu et al. Clin Pkin 14:178-
186,1988) that morphine injectcd dirtctly into thc spioal chord would give signifi-
cant analgesia. The following is a CSF concentration - time profile resulting from
05 mg/lcg IV bolus dose of Morphine:
(min) (mg/L) (min) (mg/L)
2 251 120 323
5 181 240 173
10 142.5 360 82
20 1043 480 2.4
40 75.1 720 1.2
80 48.8
1 a) fraction of remaining drug contained in peripheral compartment at equilib-
rium. Lb) Can this drug be approximated by a one compartment model ? Support
your contention with calculations. Lc) Calculate a rcasonable dosage regimen for
the above patient to maintain the concentration within the therapeuticwindow of
50 to 5 mg/L.
Two compartment:
(1) It has been proposed that diazepam has anticonvulsant properties above 350
nanograms per milliliter. The following is a concentration - time profile resulting
from 10 mg IV bolus dose of diazepam :
time conc. time
(hrs) (ng/ml)(hrs)
0.25 480 6.0
0-50 400 8.0
l.o 300 10.0
2.0 170 16.0
3.0 120 24.0
o n llo
l.a) fraction of remaining compartment at equilibrium.
n
~ _
conc.
(ng/ml)
100
90
85
70
53
Dlezzewm
UA tD 20A AD
Time
drug contained in peripheral
k21 = (1.05 * 116.8) + (0.0325 * 487.6) / (487.6 + 116.8)
= 138.5 / 604.4
= 0.239
klO = (1.05 * 0.0325) / 0.239
= n ls
kl2 = 1.05 + 0.0325 - 0.15 - 0.239
= n 7
B2 = (0.7 * lOOOOmic) / (1.05 - 0.0325)
= 6880
V1 = lOOOOmic / 604.4 mic/l
= 16.55
X2 / total = 6880 / t6880 + (16.55 * 116.8mic/1)]
= 0.78
l.b) Can this drug be approximated by a one compartment model? Support your
contention with calculations.
AUC = (487.6 / 1.05) + (116.8 / 0.0325)
= 464.4 + 3594.8
= 4058.2
Since the beta phase contributes more than 80% of the total AUC, the model can
be collapsed to a one compartment model.
3594.8 / 4058.2 = 0.886 = 89%
l.c) Calculate a reasonable dosage regimen for the above patient to maintain the
concentration within the therapeutic window of 350 to 1100 nanograms per ml.
K = 1/MRT = 1 / (111007 / 4058.2) = 1/27.35 = 0.0253 per hr
t 1/2 = 0.693 / 0.0253 = 27.39 hr
2^N^ = 1100 / 350 = 3.14
N = ln 3.14 / ln 2 = 1.65
Tau max = 27.39 * 1.65 = 45.19 hr drop the dosing interval to 24 hours now need
to find a new N
N = 24 / 27.39 = 0.876
Vss = lOOOOmic / (4058.2mic*hr/1 * 0.0253/hr) = 97.25L
To find dose:
l.lOOmg/L = (D / 97.25 L) * tl / (1 - 0.5^0.876^)]
D = 49 mg daily (aggressive therapy)
0.350mg/L = (D / 97.25L) * t 1 / (1 - 0.5^0.876^)](0.5^0.876^)
D = 29 mg daily (conseervative therapy)
Therefore, any dose between 30 and 50 mg a day can be given.
Two Compartment:
We have used theophylline as a test drug in many of our calculations in class. We
assumed that it was a one compartment model. Look at the data from Mitenko
(Clin Pharmacol and Ther,14p509 1974) for intravenous theophylline (Dose 5.6
mg/kg):
sos
theophylilne
.
i ,_
1.
O D 2D 4wD 6D8S tD
Tlm~
Time (hr.)
0.167
0.333
0.500
0.833
1.0
1.5
2.0
3.0
4.0
6.0
8.0
Conc. (mg./L.)
24.7 Estimates of Pharmacokinetic parameters
20.3 are as follows:
18.1 A1 (mg/L)16.1
16.1 B1 (mg/L)17.9
15.6 Alpha (hr-l)4.8
14.3 Beta (hr-l)0.15
13.3 AUC (O to inf) 122.7
11. AUMC (O to inf) 797.6
9.8
7.3
s.4
1) What is the volume of the central compartment (L/Kg) ?
*A) 0.165 B) 0.30 C) 0.35 D) 2.9 E) 6.1
2) What is the clearance of theophylline (L/Kg/hr) ?
A) 0.007 *B) 0.046C) 2.7 D) 22 E) 142.4
3) What is the Volume of
distribution in the beta phase (Vbeta)
(L/Kg) ?
A) 0.165 *B) 0.30C) 0.35D) 2.9E) 6.1
4) What percent of the equilibrium ?
A) 12 B) 23
dose is in the peripheral compartment at
*C) 46 D) 69 E) 92 treated as a one compartment model for
5) Can theophylline be dosing purposes ?
A) No, a larger percentage of the drug is in the peripheral compartment.
B) NO, A1 and C) Yes, alpha D) Yes, the approximately
*E) Yes, the approximately
B1 are about the same value. is bigger than beta contribution of the alpha phase
AUC is the total AUC. contribution of the beta the total AUC.
phase AUC is
6) What is the mean residence time (MRT) for the IV dose (hr) ?
A) 4.25 B) 5 C) 5.75*D) 6.5E) 7.25
For the same dose of an oral product information was obtained:
AUC (O to inf)
AUMC (O to inf)
7) What is the MRT for the
A) 8.0 B) 8.75
122
1400
(TheoDur^TQ^T) the following
oral dose (hr) ?
C) 9.5 D) 10.25*E) 11.5
8) What is the mean absorption time (MAT) for the oral dose (hr)?
A) 1 B) 2 C) 3 D) 4 *E) 5
9) What is the absorption rate constant for theophylline in TheoDur
(hr^T-l^T) ?
A) 0.14 B) 0.17 *C) 0.2 D) 0.25 E) 0.3
Two compartment: The following pharmacokinetic information was obtained from
EA, a
45 y/o, 70 kg, healthy male following an800 mg IV dose of
vancomycin:
A1 60 mg/L
alpha 1.33 hr^-l
B1 20 mg/L
beta 0.129 hr^-l
AUC (mg/L * hr)200
AUMC (mg/L)1237
5) What is your patients vancomycin clearance(L/hr)?
a) 0.25 *b) 4 c) 24.74 d) 45.1 e) 155
6) What is your patients V(beta)(L)?
a) 10 b) 24.74 *c) 31 d) 45.1 e) 60
7) What is your patients V1(L)?
*a) 10 b) 24.74 c) 31 d) 45.1 e) 60
8) What is your patients MRT(iv) (hr)?
a) 0.112 b) 0.162 c) 1.39 d) 4.29 *e) 6.19
9) What is your patients effective rate of elimination (hr^-l)? a) 0.112 *b) 0.162 c)
0.5 d) 4.29 e) 6.19
10) What is your patients Vss (L)?
a) 10 *b) 24.74 c) 31 d) 45.1 e) 60
11) Following an IM dose of vancomycin, the MRT(im) was calculated to be 8.185
hr. What was the absorption half life (hr)? a) 0.112 b) 0.162 *c) 1.39 d) 2 e) 6.19
RP s angina was controlled on 40 mg TID of propranolol. You calculated his phar-
macokinetic parameters to be: Vd (L) = 125; T1/2 (hr) = 3.1; Qh (L/hr) = 33; Bio-
availability (f) = .7; Bound(%) = 95. Propranolol is essen^_ tially 100%
metabolized.
12) What is his Total body clearance (L/hr)? a) 1.4 b) 14 *c) 28 d) 33 e)40.3
13) What is his hepatic extraction ratio?
a) 0.042b) .42 *c) .85 d) 1 e) 1.22
14) Assuming propranolol to be rapidly absorbed, what is his Cpss
max free concentration (ng/mL)?
*a) 13.4 b) 19.2 c) 188 d) 268 e) 355
15) What is his Cpss max total(bound and free) (ng/mL)?
a) 13.4 b) 19.2 c) 188 *d) 268 e) 355
16) What is his Cpss min free (ng/mL)?
*a) 2.2 b) 3.2 c) 31.4 d) 44.8 e) 59.3
He is now suffering from renal failure. His half life went up to 3.8 hr while his
binding went up to 98.3% because of an increase in AAG, a plasma protein to
which propranolol binds.
17) What is his new clearance (L/hr)?
a) 14.4 *b) 21.7 c) 24 d) 28 e) 36.2
18) What is his new volume of distribution (L)?
a) 79 *b) 119 c) 132 d) 153 e) 199
19) What will his new Cpss max free be if we keep him on the same
regimen (ng/mL)?
*a) 5.26 b) 7.5 c) 310 d) 442 e) 554
20) What is his new Cpss max total(ng/ml) ? a) 5.26 b) 7.5 *c) 310 d) 442 e) 554
21) What is his new Cpss min free (ng/mL)?
*a) 1.23 b) 1.75 c) 72.3 d) 103 e) 129
22) The physician sees that the clearance has dropped and consequently the total
plasma concentrations have gone up. He wants to decrease to dose to 40 mg / BID.
What would you recommend? a) Sounds good to me. That will get the Cpss max
total concentration back to it was before he was sick. b) His new clearance was
marginally changed because the drug is cleared by the liver. Id leave it alone. c) I
think the change from TID to BID is a bit much. How about lowering it to 30 mg
instead of 40 mg TID. *d) We need to increase the dose, not lower it. Id recom-
mend 40 mg QID. e) We need to increase the dose, not lower it. Id recommend 80
mg QID.
Two compartment
Methotrexate is a cytolytic used for the treatment of acute leukemia and other
forms of cancer. After a a 400 mg/kg dose the following data was recorded for a 12
y/o boy.
6 360
12 70
18 15
36 2
48 1.2
60 0.46
72 036
Q(} 0.15
FIND: (5 points) a) A^V1^V =
(5 points) b) B^V1^V =
(5 points) c) Clearance =
(5 points) d) % of drug in peripheral compartment at equilibrium =
Everything.
Primidone (Mysoline^T@^T) is an effective agent in the treatment of generalized
and complex partial seizures. Although primidone has anticonmlsant activity of its
own, much of the activity comes from the conversion to one of its metabolites,
phenobarbital. For the purposes of this exam, an insignificant error will be intro-
duced bytheuse of intermittent IV caSculations instead of oralformultipledose.
Thefolloving information for primidone and phenobarbital is available:
Primiflnne. Phenabarbital
Therapeutic Range (mg/L)5 - 12 10 - 30
Bioavailabiliq (f)1 0.9
Salt factor (S)1 09
Vd (L/Kg) 0.6 0.7
T1/2 7 hr 5 days
% Excreted undhanged2520
% Metabolized75 80
% Metabolized to Phenobarbital25*~
% Metabolized (non Phenobarb-paths)50**
2.(20 pts) Please prepare a short consult for your M.D. in which you caSculate a
dosage regimen for an 80 kg
patient whidh would l~eep the plasma concentration within the therapeutic range.
Prirnidone comes as 250 mg
scored (can be broken in half) tablets. Indude your average, maximum and mini-
mum primidone as well as
phenobarbital steady-state concentrations in the consult.
3. (25 pts) The patient recently contracted mono. His liver function has been
reduced to 50 % of normal.
Would you recommend a change in your therapy ? If you would, prepare a short
consult for his M.D. as in question #2. Dont forget that changes in hepatic clear-
ance result in changes in both phenobarbital clearance 5~nfl fannation
4. (25 pts) Now that his mono has cleared up the doctor noticed that he has stenosis
of the liver as a consequence of all t_e heavy parting that he did after the kinetics
course. His liver plasma flow has been reduced to 50 % of normal. Would you rec-
ommend a dhange in therapy ? If you would, prepare a short consult for his M.D.
as in question #2. Dont forget that dhanges in hepatic dearance result in changes
in both phenobarbital dearance and formation.
11.4 Begin
11.5 Problems
Aspirin (Problem 11 - 1)
Fu, C., Melethil, S., and Mason, W., "The pharmacokinetics of aspirin in rats and the effect of buffer", Journal of Pharmacokinetics
and Biopharmaceutics, Vol. 19, (1991), p. 157 - 173.
Aspirin is an analgesic/ antipyretic commonly used to relieve minor pain and is used in such conditions as rheumatic
fever, rheumatoid arthritis, and osteoarthritis. The major metabolite of aspirin is salicylic acid. The following set of
data was collected using rats which weighed 250 - 300 g.
1. What is ?
2. What is ?
3. What is your patient's clearance?
4. What is your patients MRT?
5. What is your patient's ?
6. What is your patient's V1?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
13. What is ?
14. What is the in the peripheral compartment?
15. What percent of the dose is in the peripheral compartment at equilibrium?
16. Can this drug be treated as a one-compartment model for dosing purposes?
17. If this drug can be treated as a one-compartment model, what is K ?
PROBLEM TABLE 11 - 1. Aspirin
weight of rat 275 g
Dose 5 mg/kg IV
A
1
8.58
a 1.07
B
1
7.24
b 0.2
AUC 38.8
AUMC 116.0
Buprenorphine (Problem 11 - 2)
Ohtani, M., et al., "Pharmacokinetic analysis of enterohepatic circulation of buprenorphine and its active metabolite, norbu-
prenorphine, in rats", Drug Metabolism and Disposition, Vol. 22, (1994), p. 2 - 7.
Buprenorphine is a morphine derivative which has twice the duration of action and 30 times the potency of morphine.
Buprenorphine is partially metabolized to norbuprenorphine which is also active in the body. In this study, buprenor-
phine was given to rats weighing 280 - 300 g.
1. What is the ?
2. What is the ?
3. What is the AUC?
5. What is your patients MRT?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
13. What is ?
PROBLEM TABLE 11 - 2. Buprenorphine
Weight of rat 290 g
Dose 0.06 mg/kg IV
A
1
41
a 3.89
B
1
10
b 0.271
AUC 48.3
AUMC 135.24
17. If this drug can be treated as a one-compartment model, what is K ?
Shi, J., et al., "Pharmacokinetic-pharmacodynamic modeling of caffeine: Tolerance to pressor effects", Clinical Pharmacology
and Therapeutics, Vol. 53, (1993), p. 6 - 14.
This study looks at the cardiovascular effects of caffeine. Caffeine is known to increase blood pressure upon its with-
drawl. This study looks at how tolerance to caffeine and its pressor effects develops and disappears with time.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
13. What is ?
PROBLEM TABLE 11 - 3. Caffeine
Patient weight 80 kg
Dose 4 mg/kg oral
A
1
10.55
a 4.9
B
1
9.1
b 0.23
f 98.4 %
Cefazolin (Problem 11 - 4)
Nightingale, C., et al., "Changes in pharmacokinetics of cefazolin due to stress", Journal of Pharmaceutical Sciences, Vol. 64,
(1975), p. 712 - 714.
Cefazolin is a cephalosporin antibiotic used in the treatment of many types of infections. This study looks at the effect
of stress on the pharmacokinetics of cefazolin. The following data was approximated from the graph given in this arti-
cle.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 4. Cefazolin
Patient weight 56.3 kg
Dose 1 g IV
A
1
206.48
a 4.832
B
1
122.96
b 0.573
Ceftazidime (Problem 11 - 5)
Ackerman, B., et al., "Effect of decreased renal function on the pharmacokinetics of ceftazidime", Antimicrobial Agents and Che-
motherapy, Vol. 25, (1984), p. 785 - 786.
Ceftazidime is a cephalosporin antibiotic. This study explores the effect of compromised renal function on the pharma-
cokinetics of ceftazidime. The following data was approximated from the graph given in this article.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 5. Ceftazidime
Dose 1 g IV bolus
A
1
188
a 8.22
B
1
58.2
b 0.49
Clentiazem (Problem 11 - 6)
Shah, A., et al., "Pharmacokinetics of clentiazem after intravenous and oral administration in healthy subjects", Journal of Clini-
cal Pharmacology, Vol. 33, (1993), p. 354 - 359.
Clentiazem is an derivative of diltiazem which is under investigation for its use in the treatment of angina pectoris and
hypertension. Clentiazem blocks calcium channels resulting in a decrease in peripheral vascular resistance which sub-
sequently leads to a decrease in blood pressure.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 6. Clentiazem
Dose 20 mg IV bolus
A
1
37.52
a 2.7
B
1
16.17
b 0.078
Cocaine (Problem 11 - 7)
Levine, B. and Tebbett, I., "Cocaine pharmacokinetics in ethanol-pretreated rats", Drug Metabolism and Disposition, Vol. 22,
(1994), p. 498 - 500.
This study looks into several reports which claim that the euphoric effects of cocaine can be enhanced when taken in
conjunction with alcohol. This effect may be the result of higher cocaine blood levels or a reduced elimination of
cocaine or a combination of both.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 7. Cocaine
Weight of rat 300 g
Dose 2 mg/kg cocaine (also 1 g/ kg ethanol)
A
1
1172.6
a 0.362
B
1
462
b 0.045
1,2-Diethyl-3-Hydroxypyridine-4-One (Problem 11 - 8)
Epemolu, O., et al., "The pharmacokinetics of 1,2-Diethyl-3-Hydroxypyridine-4-One (CP94) in rats, Drug Metabolism and Dispo-
sition, Vol. 20, (1992), p. 736 - 741.
1,2-Diethyl-3-Hydroxypyridine-4-One (CP94) is an iron chelator which is orally active. It is being investigated for use
in the treatment of hemoglobinopathic disorders. In this study, rats weighing 250 - 300 g were given doses 50 mg /kg
intravenously and the following data was collected:
Assume that the rat ( which weighs 275 g) is suffering from thalassemia and his iron levels are very high. The rat is
prescribed CP94 to restore the iron levels to normal.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 8. 1,2-Diethyl-3-Hydroxypyridine-4-One
Weight of rat 275 g
Dose 50 mg/kg IV
A
1
30.9
a 2.03
B
1
8.13
b 0.38
2,2-dimethylaziridine (Problem 11 - 9)
Lalka, D., Jusko, W., and Bardos, T., "Reactions of 2,2-dimethylaziridine-type alkylating agents in biological systems II: Compar-
ative pharmacokinetics in dogs", Journal of Pharmaceutical Sciences, Vol. 64, (1975), p. 230 - 235.
The 2,2-dimethylaziridine alkylating agents are used for their antitumor capability as antineoplastic agents. In this
study, male mongrel dogs, weighing 20 - 28 kg, were each given a dose of 12 mg/kg of ethyl bis (2,2-dimethylaziridi-
nyl) phosphinate intraveneously.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 9. 2,2-dimethylaziridine
Weight of dog 24 kg
Dose 12 mg/kg IV
A
1
42
a 0.409
B
1
8.5
b 0.095
Flurbiprofen (Problem 11 - 10)
Menzel-Soglowek, S., et al., "Variability of inversion of (R)-flurbiprofen in different species", Journal of Pharmaceutical Sciences,
Vol. 81, (1992), p. 888 - 891.
Flurbiprofen is an anti-inflammatory and analgesic agent. This study compares the pharmacokinetics of the (R)-isomer
of flurbiprofen to the those of the (S)-isomer. The following data was approximated from the graph given in this arti-
cle.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 10. Flurbiprofen
Weight of rat 260 g
Dose 10 mg/kg IV
A
1
48.5
a 2.33
B
1
57.68
b 0.175
Furosemide (Problem 11 - 11)
Tilsone, W., and Fine, A., "Furosemide kinetics in renal failure", Clinical Pharmacology and Therapeutics, Vol. 23, (1978), p. 644
- 650.
Furosemide is an agent which is used for its diuretic action to treat such conditions as renal and cardiac edema. In this
study, normal subjects were given an intravenous bolus dose of 22 mg of furosemide. Blood samples were taken at var-
ious intervals and the following data was obtained:
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 11. Furosemide
Dose 22 mg IV
A
1
2.1
a 6.9
B
1
0.77 -
b 0.96
Glycyrrhizin (Problem 11 - 12)
Tsai, T., et al., "Pharmacokinetics of glycyrrhyzin after intravenous administration to rats", Journal of Pharmaceutical Sceinces,
Vol. 81, (1992), p. 961- 963.
Glycyrrhizin is a component of licorice which is proposed to have anti-inflammatory, anti-hepatotoxic, interferon-
inducing, anti-viral, and anti-ulcer activity. It also causes pseudoaldosteronism. The following data was approximated
from the graph given in this article.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 12. Glycyrrhizin
Weight of rat 275 g
Dose 20 mg/kg
A
1
91.23
a 4.16
B
1
69.90 -
b 0.43
Human Deoxyribonuclease (Problem 11 - 13)
Mohler, M., et al., "Altered pharmacokinetics of recominant human deoxyribonuclease in rats due to the presence of a binding pro-
tein", Drug Metabolism and Disposition, Vol. 21, (1993), p. 71 - 75.
Deoxyribonucleases are found in human serum, urine, and a variety of tissues. These endonucleases catalyze the
hydrolysis of DNA to oligonucleotides. It has been suggested that increased levels of serum deoxyribonucleases may
predict malignancies.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 13. Human Deoxyribonuclease
Patient weight 260 g
Dose 1 mg/kg IV bolus
A
1
19250 -
a 8.61
B
1
4897
b 0.229
Human Granulocyte Colony-Stimulating Factor (Problem 11 - 14)
Tanaka, H., and Kaneko, T., "Pharmacokinetic and pharmacodynamic comparisons between human granulocyte colony-stimulat-
ing factor purified from human bladder carcinoma cell line 5637 culture medium and recombinant human granulocyte colony-
stimulating factor produced in Escherichia coli", The Journal of Pharmacology and Experimental Therapeutics, Vol. 262, (1992),
p. 439 - 444.
Human Granulocye Colony-Stimulating Factor (hG-CSF) is used to stimulate the proliferation of precursor cells and
their subsequent differentiation in the bone marrow. This article compares the pharmacokinetics of hG-CSF produced
by two different methods. In the first method, the hG-CSF was obtained from human bladder carcinoma cell line 5637
culture medium. In the second method, the hG-CSF was produced by Escherichia coli.
1. What is ?
2. What is ?
3. What is ?
7. What is a?
8. What is b?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 14. Human Granulocyte Colony-Stimulating Factor
Weight of rat 250 g
Dose 10 g/kg IV
A
1
116.21 -
0.24 hours
B
1
99.228
1.27 hours
Hydrocortisone (Problem 11 - 15)
Derendorf, H., et al., "Pharmacokinetics and oral bioavailability of hydrocortisone", Journal of Clinical Pharmacology, Vol. 31,
(1991), p. 473 - 476.
This study looks at both the two-compartment model pharmacokinetics and the oral bioavailability of hydrocortisone.
The following data was approximated from the graph given in this article.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 15. Hydrocortisone
Dose 20 mg IV
A
1
430
a 13.1
B
1
439 -
b 0.445
Levodopa (Problem 11 - 16)
Sasahara, K., et al., "Dosage form design for improvement of bioavailability of levodopa II: Bioavailability of marketed levodopa
preparations in dogs and parkinsonian patients" Journal of Pharmaceutical Sciences, Vol. 69, (1980), p. 261 - 265.
Levodopa is an agent used in the treatment of Parkinson's disease. This study looks at various dosage forms of
levodopa and compares the pharmacokinetic parameters of each. The following data was approximated from the graph
given in this article.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 16. Levodopa
Dose 50 mg IV
A
1
8.63
a 13.3
B
1
2.97 -
b 1.14
Meropenem (Problem 11 - 17)
Chimata, M., et al., "Pharmacokinetics of meropenem in patients with various degrees of renal function, including patients with
end-stage renal disease", Antimicrobial Agents and Chemotherapy, Vol. 37, (1993), p. 229 - 233.
Meropenem is a carapenem antibiotic which has a broad spectrum of activity. It is used in the treatment of infections
caused by both Gram-positive and Gam-negative bacteria and is active against Enterobacteriaceae and Pseudomonas
aeruginosa. Meropenem is 60% renally and 40% hepatically eliminated.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 17. Meropenem
Dose 500 mg IV infusion over 40 minutes
A
1
21
a 1.85
B
1
20 -
b 0.503
N-Methylpyridinium-2-Carbaldoxime Chloride (Problem 11 - 18)
Bodor, N., and Brewster, M., "Problems of delivery of drus to the brain", International Encyclopedia of Pharmacology and Thera-
peutics, Vol. 120, (1975)
N-methylpyridinium-2-cabaldoxime chloride (2-PAM) is the drug of choice for the treatment of orgaonphosphate poi-
soning. It is mostly renally excreted. This article considers the fact that this agent is highly hydrophilic and thus has
difficulty reaching the brain. The following data was approximated from the graph given in this article.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 18. N-Methylpyridinium-2-Carbaldoxime Chloride
Weight of dog 40 kg
Dose 7.0 mg/kg
A
1
5.356
a 0.28796
B
1
35.983
b 11.586
Pyrazine Diazohydroxide (Problem 11 - 19)
Vogelzang, N., et al., "Phase I and pharmacokinetic study of a new antineoplastic agent: pyrazine diazohydroxide (NSC 361456)",
Journal of Cancer Research , Vol. 54, (1994), p. 114 - 119.
Pyrazine diabhohydroxide is an agent which forms a reactive pyrazine dizonium ion in vivo which acts to destroy
tumor cells. This study looks at the pharmacokinetic parameters of this agent in advanced cancer patients whose cancer
was not curable by any other type of therapy. They were given a dose of 18 mg/m2/day for 5 days every 4 weeks.
Most of the following data was collected for a 66 year old male subject. The remaining data was approximated from
the graph given in this article.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 19. Pyrazine Diazohydroxide
Patient Body Surface Area
1.82 m
2
Dose
18 mg/ m
2
A
1
8063
a 0.195
B
1
1186
b 0.0257
Terbinafene (Problem 11 - 20)
Kovarik, J., et al., "Dose-proportional pharmacokinetics of terbinafine and its N-demethylated metabolite in healthy volunteers",
British Hournal of Dermatology, Vol. 126, (1992), p. 8 - 13.
Terbinafene is an antifungal agent which acts by interfering with ergosterol biosynthesis. It is active against Tricho-
phyton, Epidermophyton, and Microsporum. Approximately 70% of an oral dose is absorbed. Terbinafene has an N-
demethylated metabolite which is active. The following data was approximated from the graph given in this article.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 20. Terbinafene
Dose 750 mg
A
1
2398
a 0.511 -
B
1
102 -
b 0.0222 -
Verrucarol (Problem 11 - 21)
Barel, S., Yagen, B., and Bailer, M., "Pharmacokinetics of the trichothecen mycotoxin verrucarol in dogs", Journal of Pharmace-
tuical Seciences, Vol. 79, (1990), p. 548 - 550.
Verrucarol is a toxin which is related to toxins which have anti-tumor activity. This study looks at the pharmacokinet-
ics of verrucarol in dogs. The following data was approximated from the graph given in this article.
1. What is ?
2. What is ?
3. What is ?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 21. Verrucarol
Weight of Dog 22.5 kg
Dose 0.4 mg/ kg
A
1
126.05
a 0.0415
B
1
540.58 -
b 0.00946-
2-Chloro-2-deoxyadenosine (Problem 11 - 22)
Liliemark, J. and Juliusson, G., "On the pharmacokinetics of 2-Chloro-2-deoxy-adenosine in humans", Cancer Research, Vol. 51,
(1991), p. 5570 - 5572.
Two-Chloro-2-deoxyadenosine is an antitumor agent used in the treatment of hairy cell leukemia and other lymphopro-
liferative diseases. Infusions of 0.14 mg/kg over 12 hours were administered to 12 patients with various lymphoprolif-
erative diseases for 5 consecutive days. The following data was collected:
1. What is ?
2. What is ?
3. What is ?
6. What is your patient's V
1
?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 22. 2-Chloro-2-deoxyadenosine
Dose 0.14 mg/kg over 12 hours
A
1
177.0 nM
a 1.04
B
1
21.0 nM
b 0.10
Felodipine (Problem 11 - 23)
Regardh, C., et al., "Pharmacokinetics of felodipine in patients with liver disease", Journal of Clinical Pharmacology, Vol. 36,
(1989), p. 473 - 479.
The pharmacokinetic parameters of felodipine in patients with impaired liver function were investigated in this study.
Felodipine blocks calcium channels resulting in a decrease in peripheral vascular resistance which subsequently leads
to a decrease in blood pressure. Felodipine also works as a diuretic. The bioavailability of felodipine is 15%. It is
highly (99.64%) protein bound and is eliminated almost exclusively by liver metabolism. The following data is for a
patient with liver cirrhosis:
1. What is ?
2. What is ?
3. What is ?
1
?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
Weight of dog kg
Dose mg/kg IV
A
1

a
B
1

b
Lorazepam (Problem 11 - 24)
Segal, J., et al., "Decreased systemic clearance of lorazepam in humans with spinal cord injury", Journal of Clinical Pharmacol-
ogy, Vol. 31, (1991), p. 651 - 656.
Lorazepam is a benzodiazepine which is used as an anxiolytic, an anti-convulsant, an anti-emetic, and a sedative-hyp-
notic agent.
1. What is ?
2. What is ?
3. What is ?
1
?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 24. Lorazepam
Dose 2.0 mg infused intravenously over 1 - 2 minutes
A
1
a
B
1
b
AUC
AUMC
Metronidazole (Problem 11 - 25)
Uccellini, D., Morgan, D., and Raymond, K., "Relationships among duration of infusion, dose, dosing interval, and stedy-state
plasma concentrations during intermittent intravenous infusions: studies with metronazole", Journal of Pharmacokinetics and
Biopharmaceutics, Vol. 14, (1986), p. 95 - 106
1. What is ?
2. What is ?
3. What is ?
1
?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 25. Metronidazole
Dose 1.5 g IV infusion
A
1
a 2.11
B
1
b 0.09
AUC
AUMC
Rhizoxin (Problem 11 - 26)
Graham, M., et al., "Preclinical and phase I studie with rhizoxin to apply a pharmacokinetically guided dose-escalation scheme",
Journal of the National Cancer Institute, (1991), p. 494 - 499.
Rhizoxin is a lactone which was obtained from the fungus, Rhizopus chinensis. It has anti-tumor activity
against a broad spectrum of tumor types including LOX melanoma, A549 lung tumors, and MX-1 mammary
tumors. This study looks at dosing of rhizoxin. Patients with nontreatable tumors who had a life expectancy
of more than 12 weeks were given doses of 12 mg/ m
2
. The following data was approximated from the
graph given in this article.
1. What is ?
2. What is ?
3. What is ?
1
?
7. What is ?
8. What is ?
9. What is ?
10. What is ?
11. What is ?
12. What is ?
PROBLEM TABLE 11 - 26. Rhizoxin
Patient Body Surface Area
1.82 m
2
Dose
12 mg/ m
2
A
1
1.55
a 4.00
B
1
0.12
b 0.116 -
11.5.1 TWO-COMPARTMENT MODEL EQUATIONS
The following set of equations were used to solve the two-compartment model problem set. The problem sets for the
first three drugs have been done for you. The others are done the same way. The answers for all of the problems are in
the back of this packet.
Aspirin
1.
2.
3.
4.
5. The weight of the rat is 275 g or 0.275 kg.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15. Yes
_____________________________________________________________________
Buprenorphine
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15. Yes
_____________________________________________________________________
Caffeine
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15. Yes
11.5.2 ANSWERS
Aspirin
1. 8.019
2. 36.2
3. 31.1
4. 2.62 minutes
5. 155.48 mL
6. 86.92 mL
7. 81.57 mL
8. 0.648 min
9. 3.47 min
10. 0.598 min-1
11. 0.358min-1
12. 0.314min-1
13. 15.82
14. 1.928 minutes
15. 44.1%
16. Yes
17. 0.381 min-1
Buprenorphine
1. 10.54
2. 36.9
3. 47.4
4. 366.8
5. 2.85 hours
6. 1.35 L
7. 0.34 L
8. 0.178 hours
9. 2.58 hours
10. 0.981 h-1
11. 1.075 h-1
12. 2.11 h-1
13. 51
14. 0.736 hours
15. 74.9%
16. No
17. Can't be calculated
Caffeine
1. 2.15
2. 39.57
3. 41.72
4. 7.67
5. 33.35 L
6. 16.28 L
7. 0.141 hours
8. 3.014 hours
9. 2.39 h-1
10. 0.471 h-1
11. 2.266 h-1
12. 19.65
13. 0.655 hours
14. 51.2%
15. Yes
Cefazolin
1. 42.73
2. 214.59
3. 257.32
4. 3.89
5. 6.78 L
6. 3.035 L
7. 0.143 hours
8. 1.21 hours
9. 2.163 h-1
10. 1.28 h-1
11. 1.96 h-1
12. 329.44
13. 0.50 hours
14. 55.2%
15. Yes
Ceftazidime
1. 22.87
2. 118.78
3. 141.65
4. 7.0598
5. 14.41 L
6. 4.06 L
7. 0.0843 hours
8. 1.415 hours
9. 2.32 h-1
10. 1.738 h-1
11. 4.65 h-1
12. 246.2
13. 0.365 hours
14. 39.2%
15. Yes
Clentiazem
1. 13.9
2. 207.3
3. 221.2
4. 90.4
5. 1159.2 L
6. 372.5 L
7. 0.257 hours
8. 8.89 hours
9. 0.868 h-1
10. 0.243 h-1
11. 1.67 h-1
12. 53.69
13. 1.35 hours
14. 47.4%
15. Yes
Cocaine
1. 3239.2
2. 10266.7
3. 13505.89
4. 44.43
5. 987.2 mL
6. 367.1 mL
7. 1.91 minutes
8. 15.4 minutes
9. 0.1346 min-1
10. 0.1210 min-1
11. 0.1514 min-1
12. 1634.6
13. 8.35 minutes
14. 59.2%
15. No
1,2-Diethyl-3-hydroxpyridine-4-one
1. 15.22
2. 21.39
3. 36.62
4. 375.5
5. 988.2 mL
6. 352.3 mL
7. 0.341 hours
8. 1.824 hours
9. 0.724 h-1
10. 1.066 h-1
11. 0.62 h-1
12. 39.03
13. 1.016 hours
14. 55.4%
15. No
2,2-dimethylaziridine
1. 102.7
2. 89.47
3. 192.16
4. 1498.7
5. 15.78 L
6. 5.7 L
7. 1.695 minutes
8. 7.296 minutes
9. 0.148 min-1
10. 0.263 min-1
11. 0.093 min-1
12. 50.5
13. 4.65 minutes
14. 56.5%
15. No
Flurbiprofen
1. 20.82
2. 329.6
3. 350.42
4. 7.42
5. 42.4 mL
6. 24.5 mL
7. 0.297 hours
8. 3.96 hours
9. 1.35 h-1
10. 0.303 h-1
11. 0.856 h-1
12. 106.18
13. 1.2 hours
14. 42.2%
15. Yes
Furosemide
1. 0.304
2. 0.802
3. 1.106
4. 19.88
5. 20.71 L
6. 7.67 L
7. 0.1005 hours
8. 0.722 hours
9. 2.55 h-1
10. 2.59 h-1
11. 2.71 h-1
12. 2.87
13. 0.322 hours
14. 62.99%
15. No
Glycyrrhizin
1. 21.93
2. 162.56
3. 184.5
4. 29.8
5. 69.33 mL
6. 34.13 mL
7. 0.167 hours
8. 1.61 hours
9. 2.048 h-1
10. 0.873 h-1
11. 1.67 h-1
12. 161.13
13. 0.61 hours
14. 50.8%
15. Yes
Human Deoxyribonuclease
1. 2235.78
2. 21384.3
3. 23620.1
4. 11.01
5. 48.07 mL
6. 10.77 mL
7. 0.0805 hours
8. 3.027 hours
9. 1.929 h-1
10. 1.0223 h-1
11. 5.89 h-1
12. 24147
13. 0.433 hours
14. 28.9%
15. Yes
Human Granulocyte Colony-Stimulating Factor
1. 40.24
2. 181.81
3. 222.05
4. 11.26
5. 20.62 mL
6. 11.6 mL
7. 2.89 h-1
8. 0.546 h-1
9. 1.625 h-1
10. 0.971 h-1
11. 0.839 h-1
12. 215.44
13. 0.711 hours
14. 43.8%
15. Yes
Hydrocortisone
1. 32.8
2. 986.5
3. 1019.3
4. 19.62
5. 44.1 mL
6. 23.01 mL
7. 0.053 hours
8. 1.56 hours
9. 6.838 h-1
10. 0.853 h-1
11. 5.85 h-1
12. 869
13. 0.267 hours
14. 47.8%
15. Yes
Levodopa
1. 0.649
2. 2.61
3. 3.25
4. 15.37
5. 13.48 L
6. 4.31 L
7. 0.052 hours
8. 0.61 hours
9. 4.25 h-1
10. 3.56 h-1
11. 6.62 h-1
12. 11.6
13. hours
14. 68.0%
15. Yes
Meropenem
1. 11.35
2. 39.76
3. 51.11
4. 9.78
5. 19.45 L
6. 12.20 L
7. 0.375 hours
8. 1.378 hours
9. 1.16 h-1
10. 0.802 h-1
11. 0.391 h-1
12. 41
13. 0.967 hours
14. 37.3%
15. No
N-methylpyridinium-2-carbaldoxime chloride
1. 18.6
2. 3.106
3. 21.71
4. 12.9
5. 1.11 L
6. 6.77 L
7. 2.41 hours
8. 0.0598 hours
9. 1.752 h-1
10. 1.905 h-1
11. 8.218 h-1
12. 41.339
13. 0.327hours
?14. 45.5%
15. Yes
Pyrazine Diazohydroxide
1. 41348.7
2. 46147.9
3. 87496.6
4. 0.3744
5. 14.57 mL
6. 3.542 mL
7. 3.55 minutes
8. 26.97 minutes
9. 0.0474 min-1
10. 0.106 min-1
11. 0.0676 min-1
12. 9249
13. 11.97 minutes
14. 75.7%
15. No
Terbinafene
1. 4692.8
2. 4594.6
3. 9287.4
4. 80.75
5. 3637.6 L
6. 300 L
7. 1.36 h
8. 31.2 h
9. 0.0421 h-1
10. 0.2692 h-1
11. 0.222 h-1
12. 2500
13. 6.42 hours
14. 91.8%
15. No
Verrucarol
1. 3037.35
2. 57143.8
3. 60181.1
4. 149.5
5. 15.81 L
6. 13.5 L
7. 16.7 minutes
8. 73.3 minutes
9. 0.0155 min-1
10. 0.0253 min-1
11. 0.0101 min-1
12. 666.63
13. 46.15 minutes
14. 28.1%
15. Yes
CHAPTER 12 Protein Binding
OBJECTIVES
2.
CHAPTER 13 Nonlinear (Michaelis-Menton)
Kinetics
OBJECTIVES
1. Given population average patient data, the student will devise (V) a dosage regi-
men which will maintain plasma concentrations of drug within the therapeutic
range.
2. Given specific patient information, the patient will justify (VI) the optimal dosage
regimen.
3. Given patient information regarding organ function, the student will devise (V)
and justify (VI) dosage regimens for the compromised patient.
Nonlinear (Michaelis-Menton) Kinetics
13.1 Problems
Cefadroxil (Problem 11 - 27)
Sanchez-Pico, A., et al, "Nonlinear intestinal abosrption kinetics of cefadroxil in the rat", Journal of Pharmacy Pharmacology,
Vol.41, (1989), p. 179 - 185.
Cefadroxil is a cephalosporin antibiotic which is commonly used to treat various infections. It is usually given orally.
This study looks at the pharmacokinetics and bioavailability of cefadroxil in the rat.
Find .
Find the maximum clearance,, for this patient.
What would be the dose needed to acheive a steady-state concentration of 10 ?
You recommend changing the patient's dosage regimen to 300 mg/day. What would be your patient's steady state
plasma concentration?
PROBLEM TABLE 11 - 27. Cefadroxil
Dose
500 mg 7.31
1000 mg 14.67
CD4 (Problem 11 - 28)
Qian, M., et al., "Pharmacokinetic evaluation of drug interactions with anti-human immunodeficiency virus drugs: V. effect of sol-
uble CD4 on 2',3'-dideoxycytidine kinetics in monkeys", Drug Metabolism and Disposition, Vol. 20, (1992), p. 396 - 400.
2',3'-dideoxycytidine in combination with recombinant ST4 has been shown to be effective against HIV (human immu-
nodeficiency virus) in vitro. This study examines whether or not the pharmacokinetics of 2',3'-dideoxycytidine are
affected by administration of CD4 (an immunoglobulin). Doses of each drug were given to male adult monkeys
weighing an average of 4.45 kg. The following data is for ST4 (soluble CD4).
Find .
Find the maximum clearance for this patient.
You recommend changing the patient's dosage regimen to 1.5 mg/ kg. What would be your patient's plasma concentra-
tion?
PROBLEM TABLE 11 - 28. CD4
Dose
1.1 mg/kg 10.27
2.2 mg/kg 22.23
Weight of Monkey = 4.45 kg
Methylprednisone (Problem 11 - 29)
Haughey, D, and Jusko W.., "Bioavailability and nonlinear dispositionof methylprednisolone and methylprednisone in the rat",
Journal of Pharmaceutical Sceicnes, Vol. 81, (1992), p. 117 - 121.
Methylprednisone is a corticosteroid which is commonly used in the treatment of medical emergencies such as cardio-
vascular shock, asthma, and cerebral edema. The following data was obtained for two methylprednisolone doses. The
plasma concentration measurement given for each dose below is that for the central compartment.
Find .
Find the maximum clearance for this patient.
What would be the dose needed to acheive a steady-state concentration of 10,000 ?
You recommend changing the patient's dosage regimen to 30 mg. What would be your patient's plasma concentration?
PROBLEM TABLE 11 - 29. Methylprednisone
Dose
10 mg 6834
50 mg 71519
Mezlocillin (Problem 11 - 30)
Jungbluth, G. and Jusko, W., "Dose-dependent pharmacokinetics of mezlocillin in rats", Antimicrobial Agents and Chemotherapy,
Vol. 33, (1989), p. 839 - 843.
Mezlocillin is an antibiotic used to treat various types of infection. It is usually given by the intravenous route and
exhibits dose-dependent (nonlinear) pharmacokinetics. This article compares two intravenous bolus doses, one of 20
mg/kg and one of 200 mg/kg in rats. The following data was calculated from the results of this study.
Find .
You recommend changing the patient's dosage regimen to 150 mg/ kg. What would be your patient's plasma concen-
tration?
PROBLEM TABLE 11 - 30. Mezlocillin
Dose
20 mg/kg 158.6
200 mg/kg 294.1
Rat weight = 425 g
Naphthol (Problem 11 - 31)
Redegeld, A., Hofman, G., and Noordhoek, J., "Conjugative clearance of 1-naphthol and disposition of its glucuronide and sulfate
conjugates in the isolated perfused rat", Journal of Harmacology and Experimental Therapeutics, Vol. 244, (1988), p. 263 - 267.
1-naphthol is a small phenolic compound which is extensively metabolized by conjugation. This study looks at the
pharmacokinetics of naphthol in a rat.
Find .
What would be the dose needed to acheive a steady-state concentration of 7.7 M?
You recommend changing the patient's dosage regimen to 35 mol. What would be your patient's plasma
concentration?
PROBLEM TABLE 11 - 31. Naphthol
Dose
30 mol 6.79 M
40 mol 8.63 M
Paroxetine (Problem 11 - 32)
Sindrug, S., Brosen, K, and Gram, L.., "Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: nonlinearity
and relation to the sprateine oxidation polymorphism", Clinical Pharmacology and Therapeutics, Vol. 51, (1992), p. 288 - 295.
Paroxetine hydrochloride (Paxil) is a selective serotonin reuptake inhibitor which is used in the treatment of
depression. Paroxetine is metabolized both by oxidation and conjugation with the conjugated metabolites
excreted in the urine. Paroxetine exhibits dose-dependent (nonlinear) pharmacokinetics. The following
data is for a male diabetic patient who was concurrently taking insulin.
Find .
You recommend changing the patient's dosage regimen to 36 mg/day. What would be your patient's plasma concentra-
tion?
PROBLEM TABLE 11 - 32. Paroxetine
Dose
10 mg daily 1.65
20 mg daily 3.30
30 mg daily 8.25
40 mg daily 13.20
50 mg daily 26.40
60 mg daily 39.60
70 mg daily 66.00
Phenytoin (Problem 11 - 33)
Levine, M., et al., "Evaluation of serum phanyton monitoring in an acute care setting", Therapeutic Drug Monitoring, Vol. 10,
(1988)., p. 50 - 57.
Phenytoin is an agent which is commonly used in the treatment of epilepsy. This drug exhibits nonlinear kinetics.
Phenytoin is mainly eliminated from the body by hepatic cytochrome P-450 metabolism. Several doses of phenytoin
were studied in patients and the data is summarized below:
Find .
You recommend changing the patient's dosage regimen to 300 mg/day. What would be your patient's plasma concen-
tration?
PROBLEM TABLE 11 - 33. Phenytoin
Dose Day
300 mg at bedtime
(started on day 1)
2 5.0
200 mg BID
(started on day 6)
12 11.4
200 mg BID
(started on day 6)
49 21.5
Phenytoin in the Critically Ill (Problem 11 - 34)
Boucher, B. et al., "Phenytoin pharmacokinetics in critically ill trauma patients", Clinical Pharmacology and Therapeutics, Vol.
44, (1988)., p. 675 - 683.
Phenytoin is an agent which is commonly used in the treatment of epilepsy. This drug exhibits nonlinear kinetics. This
study looks at several doses of phenytoin in severely ill trauma patients. The data given below is that obtained for one
male, 25 year-old, patient who weighed 85 kg.
Find .
What would be the dose needed to acheive a steady-state concentration of 12?
You recommend changing the patient's dosage regimen to 450 mg/ day. What would be your patient's steady-state
PROBLEM TABLE 11 - 34. Phenytoin in the Critically Ill
Dose
615 mg/ day 10
588 mg/day 8.5
Phenytoin in Pediatrics (Problem 11 - 35)
Bauer, L. and Blouin, R., "Phenytoin Michaelis-Menten pharmacokinetics in caucasian paediatric patients", Clinical Pharmacoki-
netics, Vol. 8, (1989)., p. 545 - 549.
Phenytoin is an agent which is commonly used in the treatment of epilepsy. This drug exhibits nonlinear kinetics. This
study looks at several doses of phenytoin in pediatric patients of several ages. The data for the 4 to 6 year old patients
is given below.
Find .
You recommend changing the patient's dosage regimen to 4.5 mg/ kg/ day. What would be your patient's steady-state
Dose
7.5 mg/ kg/ day 15
6.5 mg/ kg/day 10
Quinalapril (Problem 11 - 36)
Elliott, H., et al., "Dose responses and pharmaockinetics for the angiotensin converting enzyme inhibitor, quinapril", Clinical
Pharmacology and Therapeutics, Vol. 52, (1992), p. 260 - 265.
Quinalapril is an angiotensin converting enzyme (ACE) inhibitor which is used in the treatment of hypertension and
heart failure. The optimal dosage regimen for the ACE inhibitors is controversial and this study further investigates
quinalapril's pharmacokinetics at various doses ranging from 0.5 to 20 mg. Quinalapril is a prodrug which is metabo-
lized to its active form, quinalaprilat.
Find .
You recommend changing the patient's dosage regimen to 3.0 mg/day. What would be your patient's plasma concen-
tration?
Dose
(of quinalapril) (of quinalaprilat)
2.5 mg daily 47.5
5.0 mg daily 98.1
Vanoxerine (Problem 11 - 37)
Ingwersen, S., et al., "Nonlinear multiple-dose pharmacokinetis of the dopamine reuptake inhibitor vanoxerine", Journal of Phar-
maceutical Sciences, Vol. 82, (1993)., p. 1164 - 1166.
Vanoxerine is a pre-synaptic dopamine reuptake inhibitor which may be useful as an antidepressant. The bioavailabil-
ity of vanoxerine is changed by food intake. The bioavailability after fasting is increased 76% by a low-fat meal and
255% by a high-fat meal. In this study, the volunteers were given doses of vanoxerine after eating a standard breakfast
of one bowl of cereal with milk, two slices of toast with sunflower margarine and jam, and one cup of tea.
Find .
What would be the dose needed to acheive a steady-state concentration of 30.0 ?
You recommend changing the patient's dosage regimen to 100 mg. What would be your patient's plasma concentra-
tion?
Dose
25 mg 3.4
75 mg 15.1
125 mg 46.5
13.2 Nonlinear Equations
The following equations were used to solve the questions following each "nonlinear" scenario. Three scenerios have
been completed for you. The answers have been provided for the remainder.
1.
2.
3.
4.
Phenytoin in the Critically Ill
CD4
1. The monkeys had an average weight of 4.45 kg.
2.
3.
4.
Cefadroxil
1.
2.
3.
4.
13.2.1 ANSWERS
Cefadroxil
2144.75
147.2 g/day
683.14 mg
4.38
CD4
135.09
69.28 mg/day
6.92 mg/day
14.4
Methylprednisone
52345.27
86.60 mg/day
13.89 mg/day
27747.1
Mezlocillin
324.95
25.92 mg/day
68.23 mg/day
1676.04
Naphthol
46.14 (M
233.86 (mol
25.61 (mol
43.5 (M
Paroxetine
4.125
45 mg/day
41.6 mg/day
16.5
Phenytoin
4.014
540.85 mg/day
426.7 mg/day
5
Phenytoin in the Critically Ill
3.517
831.3 mg/day
642.88 mg/day
4.15
Phenytoin in Pediatrics
6.67
162.5 mg/day
104.46 mg/day
4.74
Quinalapril
1503.15
81.61 mg/day
3.88 mg/day
57.36
Vanoxerine
20.96
179.08 mg/day
105.4 mg/day
26.5
CHAPTER 14 Practice Exams: Section 1
Reviewer: Vicki Long
ORGANIZATION
Following are several exams which have been used
in previous classes. These exams cover Chapters 1
through 4. Answers (including the graphs) are
included in a format similar to real exam conditions,
and some exams have the problems worked out
completely.
You are encouraged to work out the exams under
conditions similar to how you will take the exam.
You will want to have a calculator, semi-log graph
paper, and scratch paper available. Before you
begin to answer the questions, you will want to: 1)
create the model from the description of the drugs
pharmacokinetics, 2) graph all of the data as dis-
cussed in the chapters. From these graphs the
answers will become available. Your graphs should
look like the graphs included in the answers. Appli-
cable equations vary by exam and are included at the
beginning of each chapter covered by the exam.
Remember where you are in the course: Learn the
tools; get the pharmacokinetic parameters from
patient information. So in this section you must be
able to analyze pharmacokinetic data and extract the
pharmacokinetic parameters. That means: Assess
the pharmacokinetic description of the drug and cre-
Practice Exams: Section 1
ate a model, develop equations for the model, graph
the data according to those equations, and get the
parameters out. A student commented, You mean,
all we have to do is get the slope and intercept from
a couple of graphs and tell you what they mean?
Yes, that right!
Do not just look at the graphs and the answers and
say, Yes, that makes sense. I can do this. You will
be surprised to find out that what looks easy worked
out is not so easy when it isnt.
Practice Exams: Section 1 : Nifedipine - Section 1
Copyright 1996 Michael C. Makoid All Rights Reserved http://kiwi.creighton.edu/pkinbook/
14.1 Nifedipine - Section 1
Masotti et al (J Clin Pcol 1985; 25: 27-35) and Traube et al (ibid 125-9) looked at the hemodynamic pharmacological response of
nifedipine.
14.1.1 NIFEDIPINE DATA
Nifedipine (Procardia ) is a calcium channel blocker which specifically inhibits potential-dependent channels not
receptor-operated channels, preventing calcium influx of cardiac and vascular smooth muscle (coronary, cerebral).
Calcium channel blockers reduce myocardial contractility and A-V node conduction by reducing the slow inward cal-
cium current. They are indicated in angina, cardiac dysrhythmias, and hypertension among others. Nifedipine
appears to be metabolized entirely into an inactive metabolite, an acid and subsequently further metabolized to a lac-
tone. Both the acid and the lactone are excreted into the urine and the feces.
Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (Clin Pcol Therap 1986; 40: 21-8)
reviewed the pharmacokinetics of Nifedipine. While the drug is not routinely given by IV bolus and does not strictly
conform to a one compartment model, let's treat the data as if those problems can be ignored. The following data is
offered for evaluation:
PROBLEM TABLE 11 - 1. Pharmacological Data
Fall in Diastolic
BP Cp (ng/mL) Time (hr)
Fall in Diastolic
BP
8 15 1 13.0
10 40 2 12.3
12 100 4 10.7
13 200 5 10.0
9 7.0
PROBLEM TABLE 11 - 1. Nifedipine IV Bolus Profile
Time (hr)
Cp
(mcg/L)
Cm1
(mcg/L)
Xm1f
(mg)
Xm1u
(mg)
Xm2f
(mg)
Xm2u
(mg)
0.5 24.7
1 44.4
2 139 71.8 .14 .59
4 65.6 96.5 .44 1.83 .028 .11
6 31.1 100 .77 3.25 .073 .29
8 14.6 94.7 1.1 4.65 .135 .54
12 76.5 1.69 7.10 .291 1.15
24 34 2.77 11.63 .75 2.95
7 days 3.6 15.1 1.3 5.0
14.1.2 NIFEDIPINE QUESTIONS
1) dR/dT = slope of the Pharmacological
response vs. time profile (mmHg/hr)
2) dR/d(lnC) = slope of the Pharmacolog-
ical response vs concentration profile
(mmHg)
3) d(lnC)/dt = slope of the concentration
vs time profile (hr-1 )
4) kr = rate constant of excretion of Nife-
dipine into the urine (hr-1 )
5) kf = rate constant of excretion of Nife-
dipine into feces (hr-1 )
6) km1 = rate of metabolism of Nife-
dipine in the body (hr-1 )
7) K1 = elimination rate constant of Nifedipine in
the body; the summation of all of the ways that it is
removed from the body. (hr-1 )
8) T1/2 of Nifedipine in the body (hr)
9) X0 = Mass of Nifedipine in the body
at time 0 (mg)
10) Xinf = Mass of Nifedipine in the body
at time infinite time (mg)
11) Xuinf = Mass of unchanged Nife-
dipine in the urine at infinite time (mg)
12) Xfinf = Mass of unchanged Nife-
dipine in the feces at infinite time (mg)
13) V = Volume of distribution of Nife-
dipine (L)
14) Cp0 = Concentration of Nifedipine in
the body at time 0. (mic/L)
15) AUCiv = Area under the plasma con-
centration of Nifedipine vs time curve of
the IV dose (mic/L*hr)
16) First trapazoid of the AUCiv (mic/
L*hr)
17) Last trapazoid of the AUCiv (mic/
L*hr)
18) AUMCiv = Area under the first moment
of the plasma concentration of Nifedipine vs
time curve of IV dose (mic/L*hr2 )
19) MRTiv = Mean Residence time of
Nifedipine given as the IV dose (hr)
20) Xm10 = Mass of acidic metabolite in
the body at time = 0 (mg)
21) Xm1inf = Mass of the acidic metabo-
lite in the body at infinite time. (mg)
22) Vm1 = Volume of distribution of the
acidic metabolite in the body (L)
23) Cm1 = Concentration of acidic metab-
olite in the body at time = 0 (mic/L)
Im1 = Intercept of the acidic metabolite con-
centration vs time profile = 181.2 mic/L
24) AUCmet = Area Under the Curve of
the metabolite plasma concentration vs
time profile (mic/L*hr)
AUMCmet = Area Under the First Moment
Curve of the metabolite plasma concentration vs
time profile = 35700 mic/L*hr2
25) Xm1u0 = Mass of acidic metabolite
in urine at time = 0 (mg)
26) Xm1uinf = Mass of acidic metabolite
in urine at time = infinity (mg)
27) Xm1f0 = Mass of acidic metabolite in
feces at time = 0 (mg)
28) Xm1finf = Mass of acidic metabolite
in feces at time = infinity (mg)
29) Km1u = Rate constant of excretion of
acidic metabolite into urine (hr-1 )
30) Km1f = Rate constant of excretion of
acidic metabolite into feces (hr-1 )
31) Km2=Rate constant of formation of
lactone metabolite in body =rate of metabolism of
the acidic metabolite in the body (hr-1 )
32) K2 = Km1f + Km1u + Km2 = sumation of
all of the ways that the acidic metabolite is eliminated from the
body (hr-1 )
33) Xm20 = Mass of lactone metabolite
in body at time = 0 (mg)
34) Xm2inf = Mass of lactone metabolite
in body at time = infinity (mg)
35) Cm2inf = Concentration of lactone
metabolite in the body at time = infinity (0)
36) Xm2u0 = Mass of lactone metabolite
in urine at time = 0 (mg)
37) Xm2uinf = Mass of lactone metabo-
lite in urine at time = infinity (mg)
38) Xm2finf = Mass of lactone metabolite
in feces at time = infinity (mg)
K3 = Km2f + Km2u = the sumation of all of
the ways that the lactone can be eliminated =
0.138 hr.-1
39) Km2u = Rate constant of excretion of
lactone metabolite into urine (hr -1 )
40) Km2f = Rate constant of excretion of
lactone metabolite into feces (hr -1 ) .
PROBLEM TABLE 11 - 1. Answer Pool Any number from the answer pool may be used
once, more than once, or not at all
Negative Numbers Small Numbers Big Numbers
A -0.0001 0 13
B -0.0010 0.010 15.1
C -0.0100 0.018 17
D -0.0180 0.028 20
E -0.0280 0.042 25
F -0.0375 0.070 38.9
G -0.0750 0.085 50
H -0.0850 0.110 85
I -0.110 0.138 170
J -0.138 0.375 181.2
A -0.375 0.750 295
B -0.750 1.30 415
C -1.30 1.85 434
D -1.85 2.0 787
E -2.0 2.67 2100
F -2.67 3.6 3570
G -3.6 5.0 8500
H -5.0 7.5 21000
I -7.5 8.5 35700
J -10 9.9 85000
14.1.3 NIFEDIPINE SOLUTIONS
X
Xm1
Xm2
Xmf1
Xmf2
Xmu1
Xmu2
km1
km2
kmu1
kmu2
kmf1
kmf2
Nifedipine
Concentration (ng/mL)
R
e
s
p
o
n
s
e

(
m
m
H
g
)

10
1
10
2
10
3
8
9
10
11
12
13
14
0 2 4 8 10
6
7
8
9
10
11
12
13
14
R vs T
Time (hr)

6
R
E
S
P
O
N
S
E

(
M
M
H
G
)
Graph #2
Graph #1
- 0.75 mmHg/hr
2 mm Hg
Nifedipine IV Bolus
Time (hours)
L
)

2 3 4 5 6 7 8
10
1
10
2
10
3
Nifedipine IV bolus - Metabolite
Time (hours)
/
m
L
)

0 4 8 12 16 20 24
10
1
10
2
10
3
1.85 hr
100
50
Graph #3
181.2 mic/L = Intercept (given)
Graph #4
10 hrs
C
O
N
C
E
N
T
R
A
T
I
O
N

M
I
C
/
L
C
O
N
C
E
N
T
R
A
T
I
O
N

M
I
C
/
L
1. Slope from graph # 2
2. Slope from graph # 1
3.
4. k
r
= 0, Nifedipine is not excreted into the urine, it is metabolized entirely from pkin description
5. k
f
= 0, Nifedipine is not found in the feces, only the metabolites are. from pkin description
6. k
m1
, Rate of metabolism of Nifedipine in the body = from graph #3
7. K1, Elimination rate constant of Nifedipine in the body = from graph #3
8. = 1.85 hr from graph #3
9. from pkin description =
10. from pkin description
13.
14. Cp
0
extrapolated back to t = 0 obtained from graph #3
15. as an estimate. Using Trapazoidal rule:
dR
dT
------- 0.75mmHg hr =
dR
d C ln
------------ 2.0mmHg =
d C ln
dT
------------
dR
dT
-------
dR
d C ln
------------
------------- =
0.75
2
------------- 0.375hr
1
= =
Answer #1
Answer #2
--------------------------
K1 k
m1
=
K1 k
m1
=
0.693
1.85hr
---------------- 0.375 = hr
1
0.375hr
1
T
1 2
X
o
3.6 15.1 1.3 5.1 + + + ( ) 25mg = = X
mu1
X
mu2
X
mf 1
X
mf 2
+ + + ( )
X
inf
0 =
X
u inf ( )
0 =
X
f inf ( )
0 =
V
Dose
Cp
o
-------------
25mg
295mic L
--------------------------
1000mic
1mg
--------------------- 85L = = =
295mic L
AUC
iv
Cp
o
k
---------
295
0.375
------------- 787mic L hr = = =
Cp
o
Cp
1
+
2
-------------------------- t
1
Cp
1
Cp
2
+
2
-------------------------- t
2
Cp
2
Cp
3
+
2
-------------------------- t
3
Cp
3
Cp
last
+
2
------------------------------- t
last
Cp
last
K1
--------------- + + + +

' ;

295 139 +
2
------------------------ 2
139 65.6 +
2
------------------------- 2
65.6 31.1 +
2
--------------------------- 2
31.1 14.6 +
2
--------------------------- 2
14.6
0.375
------------- + + + +

' ;

mcg
L
----------hr
434 204.6 96.7 45.7 38.9 + + + + { }
mcg
L
----------hr 821.9
mcg
L
----------hr =
16
17.
18 estimate. Using the trapazoidal rule:
19. estimate. Using trapazoidal rule and definitions
22.
From LaPlace transforms, the equation for the metabolite is
the intercept, I, given as 181.2 mic/L in the data = .
Thus
Cp
o
Cp
1
+
2
-------------------------- t
295 139 + ( )
2
----------------------------- 2
,
_
434mic L hr = =
Cp
L
k
----------
14.6
0.375
------------- 38.9mic L hr = =
AUMC AUC MRT 787 2.67 2100mic L hr
2
= = =
T
0
C p
o
T
1
C p
1
+
2
----------------------------------------------- t
1
T
1
C p
1
T
2
C p
2
+
2
----------------------------------------------- t
2
T
2
C p
2
T
3
C p
3
+
2
----------------------------------------------- t
3
T
3
C p
3
T
last
C p
last
+
2
---------------------------------------------------------- t
last
T
last
C p
last
K1
-------------------------------
Cp
last
K1
2
--------------- + + + + +

' ;

0 295 2 139 +
2
--------------------------------------- 2
2 139 4 65.6 +
2
---------------------------------------- 2
4 65.6 6 31.1 +
2
------------------------------------------ 2
6 31.1 8 14.6 +
2
------------------------------------------ 2
8 14.6
0.375
------------------
14.6
0.375
2
---------------- + + + + +

' ;

mcg
L
----------hr
2
278 540.4 449 303.4 311.47 103.82 + + + + + { } 1986.1
mcg
L
----------hr
2
=
MRT
iv
1
k
--- 2.67hr = =
MRT
IV
AUMC
trap
AUC
trap
---------------------------
1986.1
mcg
L
----------hr
2
821.9
mcg
L
----------hr
------------------------------------ 2.42 hr
AUMC
est
AUC
est
------------------------
2100
mcg
L
----------hr
2
787
mcg
L
----------hr
------------------------------- 2.67 hr = = = = =
X
m1 o ( )
0 =
X
m1 inf ( )
0 =
V
m1
170L =
Cp
m
k
m1
X
0
K1 K2 ( ) V
dm
---------------------------------------- e
K2t
e
K1t
{ } =
k
m1
X
0
K1 K2 ( ) V
dm
----------------------------------------
V
dm
k
m1
X
0
K1 K2 ( ) 181.2
mic
L
---------
-----------------------------------------------------
0.375 25mg
0.375 0.07 ( ) 0.1812
mg
L
-------
---------------------------------------------------------------- 169.6 L = = =
C
m1 0 ( )
0 =
24.
26. given in data
28. given in data
29. thus
30. thus
31.
PROBLEM TABLE 11 - 1. Nifedipine Data
Time (hr) Cpm (mcg/L)
0 0
0.5 24.7 0.5 6.175 6.175
1 44.4 0.5 17.275 23.45
2 71.8 1 58.1 81.55
4 96.5 2 168.3 249.85
6 100 2 196.5 446.35
8 94.7 2 194.7 641.05
12 76.5 4 342.4 983.45
24 34 12 663 1646.45
0
+
485.7 2132.15
AUC
met
2100mic L hr =
Cpm n ( ) Cpm n 1 + ( ) +
2
--------------------------------------------------------
T n ( ) AUC
t
trap
AUC
0
t
0 24.7 +
2
-------------------
24.7 44.4 +
2
---------------------------
44.4 71.8 +
2
---------------------------
71.8 96.5 +
2
---------------------------
96.5 100 +
2
-------------------------
100 94.7 +
2
-------------------------
94.7 76.5 +
2
---------------------------
76.5 34 +
2
----------------------
Cpm
last
K
small
--------------------
X
m1u 0 ( )
0 =
X
m1u inf ( )
15.1mg =
X
m1f 0 ( )
0 =
X
m1f inf ( )
3.6mg =
k
m1u
0.042hr
1
=
k
m1u
K
2
-----------
X
m1u
X
o
------------
k
m1u
0.07hr
1
--------------------
15.1mg
25mg
------------------ = = = k
m1u
0.042hr
1
=
k
m1f
0.01hr
1
=
k
m1f
K
2
----------
X
m1f
X
o
-----------
k
m1f
0.07hr
1
--------------------
3.6mg
25mg
--------------- = = = k
m1f
0.01hr
1
=
k
m2
0.018hr
1
= 0.07 hr
1
K = 2 k
m1f
k
m1u
+ k
m2
0.01 hr
1
0.042 hr
1
k
m2
+ + = + =
32. From your LaPlace Transforms, you know that the equation is bi-exponential, with one of
the slopes being K1 and the other being K2. The terminal slope of graph #4 is 0.07 hr
-1
, which is not K1 (0.375 hr
-1
).
So it must be K2.
37. given in data
38. given in data
39.
40.
K2 0.07hr
1
=
X
m2 0 ( )
0 =
X
m2 inf ( )
0 =
C
m2 inf ( )
0 =
X
m2u 0 ( )
0 =
X
m2u inf ( )
5.0mg =
X
m2f inf ( )
1.3mg =
k
m2u
0.11hr
1
=
k
m2u
0.138hr
1
-----------------------
k
m2u
K3
-----------
X
m2u
X
m2u
X
m2f
+
-----------------------------
5.0mg
5.0mg 1.3mg +
------------------------------------- = = =
k
m2f
0.028hr
1
=
k
m2f
0.138hr
1
-----------------------
k
m2f
K3
----------
X
m2f
X
m2u
X
m2f
+
-----------------------------
1.3mg
5.0mg 1.3mg +
------------------------------------- = = =
Practice Exams: Section 1 : Enalapril - Section 1
14.2 Enalapril - Section 1
Citation
14.2.1 ENALAPRIL DATA
Enalapril (Vasotec ) is an angiotensin converting enzyme (ACE) Inhibitor effective in the treatment of hypertension
and chronic heart failure (CHF). The parent compound is weakly active, while its sole metabolite, Enalaprilat, exhib-
its almost all of the pharmacological activity. Original work on the pharmacokinetics of Enalapril showed the parent
drug, Enalapril and its metabolite, Enalaprilat, show up in both feces and urine.
The following data was offered regarding the Pharmacological response of Enalaprilat as judged by the fall in Seated
Systolic Blood Pressure (SSBP).
PROBLEM TABLE 11 - 1. Enalapril - Section 1: Pharmacological Profile
Fall in SSBP
(mmHg)
Time (hr) after
Max Dose (mg)
Fall in SSBP
(mmHg)
15 3 1 0
12 7 5 1
10 10 10 5
8.6 12 15 10
6 18 20 16
4 24 25 20
30 24
PROBLEM TABLE 11 - 1. Enalapril - Section 1 IV Bolus Profile from a 5 mg dose
Time
(hr)
Cp
(ng/mL)
Cpm
(ng/ml)
Cumulative
Enalapril in
urine (mg)
Cumulative
Enalapril
in feces
(mg)
Cumulative
Enalaprilat
in urine
(mg)
Cumulative
Enalaprilat
in feces
(mg)
1 29 7.5 0.41 0.12
2 17 11.6 0.65 0.20
3 10 13.8 0.80 0.24
4 5.9 14.9 0.88 0.26
6 2 15.2 0.96 0.30
8 14.7
10 13.8
20 9.8
30 6.9
40 4.9
50 3.4 1.0 0.3 2.25 1.45
The intercept of vs was found to be 19.8 and a total of 2.25 of enalaprilat was found in the
urine while 1.45 was found in the feces.
Equation Answer Pool:
A B
C D.
E F
G H
I J
PROBLEM TABLE 11 - 1. Enalapril Answer Pool
Negative
Numbers
Small
Numbers
Small
Numbers
Medium
Numbers
Large
Numbers
A 0.000 0.014 1.00 14.5 100
B -0.014 0.021 1.45 19.8 174
C -0.021 0.030 .1.90 30.3 528
D -0.030 0.035 2.25 33.0 395
E -0.035 0.039 3.75 37.5 693
F -0.110 0.110 5.00 39.5 834
G -0.390 0.150 6.93 50.0 1740
H -0.530 0.300 8.00 70.0 5280
I -0.700 0.390 9.00 94.0 14400
J -0.900 0.530 9.76 97.0 16000
Cp
m
t ng mL mg
mg
k
mu
k
m
X
o
K1 K2 ( )
-------------------------
1 e
K2t
K2
---------------------
1 e
K1t
K2
---------------------
k
mf
k
m
X
o
( )
K1 K2 ( )
-------------------------
1 e
K2t
K2
---------------------
1 e
K1t
K1
---------------------
k
m
X
0
K1 K2 ( ) Vd
m
----------------------------------------
e
K2t
( ) e
K1t
( )
k
mu
k
m
X
o
K1 K2 ( )
-------------------------
e
K2t
( ) e
K1t
( )
k
m
X
0
K1 K2 ( )
-------------------------
e
K2t
( ) e
K1t
( )
X
0
V
------e
K1t
k
r
X
0
e
K1t
k
f
K1
------- X
0
1 e
K1t
( )
k
u
K1
------- X
0
1 e
K1t
( ) X
0
e
K1t
14.2.2 ENALAPRIL QUESTIONS
Find the equation for:
1) X, the mass of parent drug, Enalapril, in
the body.
2) X
u
, the mass of parent drug, Enalapril,
in urine.
3) dX
u
/dt, the rate of excretion of parent
drug, Enalapril, in urine.
4) X
f
, the mass of parent drug, Enalapril, in
feces.
5) X
m
, the mass of metabolite, Enalaprilat,
in the body.
6) X
mu
, the mass of metabolite, Enalapri-
lat, in urine.
7) dX
mu
/dt, the rate of excretion of metab-
olite, Enalaprilat, in urine.
8) X
mf
, the mass of metabolite, Enalapri-
lat, in feces.
9) C
p
, the plasma concentration of parent
drug, Enalapril.
10) C
pm
, the plasma concentration of
metabolite, Enalaprilat.
Find the value of:
11) dR/dT
12) dR/d(ln(C))
13) d(ln(C))/dT
14) kr, the renal excretion rate constant of
parent drug, Enalapril, in plasma.
15) kf, the fecal excretion rate constant of
parent drug, Enalapril, in plasma.
16) km, the metabolism rate constant
ofparent drug, Enalapril, in plasma.
17) kmu, the renal excretion rate constant
for metabolite, Enalaprilat, in plasma.
18) kmf, the fecal excretion rate constant
for metabolite, Enalaprilat, in plasma.
19) K1, the elimination rate constant of
parent drug in plasma(the summation of all
processes which remove Enalapril)
20) K2, the elimination rate constant of
metabolite in plasma(the summation of all
processes which remove Enalaprilat).
Find the intercept of the graph of:
21) C
p
vs T
22) C
pm
vs T (terminal extrapolated line)
23) dX
u
/dt vs T
24) dX
f
/dt vs T
Find the slope of the terminal portion of
the graph of:
25) C
p
vs T
26) C
pm
vs T
27) dX
u
/dt vs T
28) dX
f
/dt vs T
Find the area under the curve of the
graph of
29) C
p
vs T(first trapazoid only)
30) C
pm
vs T(first trapazoid only)
31) C
p
vs T(from Tlast to only)
32) C
pm
vs T(from Tlast to only)
33) C
p
vs T
34) C
pm
vs T
35) dX
u
/dt vs T
T

36) dX
mu
/dt vs T
37) T*C
p
vs T
38) T*C
pm
vs T
Find the value of :
39) AUC(enalapril)
40) AUMC(enalapril)
41) MRT(enalapril)
42) AUC(enalaprilat)
43) AUMC(enalaprilat)
44) MRT(enalaprilat)
45) X
0
46) X
U0
47) X
F0
48) X
M0
49) X
MU0
50) X
MF0
51)
52)
53)
54)
55)
56)
57) C
p0
58) C
pm0
59) V
d
60) V
dm
14.2.3 ENALAPRIL SOLUTIONS
Enalapril Model
X
X
u
X
f
X
m
X
mu
X
mf
X Xu
Xmu
Xmf
Xf
Xm
kr
km
kf
kmu kmf
2 4 6 8 10 12
Time (hr)
8
9
10
11
12
13
14
15
s
p
o
n
s
e
R vs T
10 10
Concentration
10
12
14
16
18
20
22
24
e
s
p
o
n
s
e
R vs C
RESPONSE DATA
0 1 2 3 4 5 6
Time (hrs)
10
0
10
1
10
2
C
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
L
)

Enalapril
Enalapril IV Bolus - Metabolite
Time (hours)
C
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
L
)

0 10 20 30 40 50
10
0
10
1
10
2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
X X
o
e
k1t
=
X
u
k
r
k
1
-----X
o
1 e
k1t
( ) =
dx
u
dt k
r
X
o
= e
k1t
X
f
k
f
k
1
-----X
o
1 e
k1t
( ) =
X
m
k
m
X
o
k
1
k
2
( )
--------------------- e
k2t
e
k1t
( ) =
X
mu
k
mu
k
m
X
o
k
1
k
2
( )
---------------------
1 e
k2t
k
2
--------------------
1 e
k1t
k
1
-------------------- =
dX
mu
dt
-------------
k
mu
k
m
X
o
k
1
k
2
--------------------- e
k2t
e
k1t
( ) =
X
mf
k
mf
k
m
X
o
( )
K1 K2
-------------------------
1 e
K2t
K2
---------------------
1 e
K1t
K1
--------------------- =
C
p
C
po
e
k1t D
Vd
-------e
k1t
= =
Cp
m
k
m
X
0
K1 K2 ( ) Vd
m
----------------------------------------
e
K2t
( ) e
K1t
( )
=
dR dt 0.7 =
dR d c ln ( ) 20 =
d c ln ( ) dt
0.7
20
---------- =
,
_
0.035 =
k
r
X
u
X
o
------- k
1
1
5
--- 53 0.106 0.11hr
1
= = = =
k
f
X
f
X
o
------- k
1
0.3
5
------- 0.53 0.0318 0.03 = = = hr
1
=
16
17
18
19 = slope of Cp vs T =
20 = terminal slope of graph vs T =
21
22 I = 19.8
23 vs T I = 0.53
24
25 0.53
26 0.035
PROBLEM TABLE 11 - 1. Urinary Rate Set up
0 0
0.5 1 1 0.41 0.41 0.41
1.5 2 1 0.65 0.24 0.24
2.5 3 1 0.80 0.15 0.15
3.5 4 1 0.88 0.08 0.08
5 6 2 0.96 0.08 0.04
k
m
X
mu
X
mf
+
X
o
------------------------ k
1
2.25 1.45 +
5
--------------------------- = 0.53 0.39 = hr
1
=
k
mu
X
mu
X
mu
X
mf
+
------------------------ k
2
2.25
3.7
---------- 0.035 0.21hr
1
= = =
k
mf
X
mf
X
mu
X
mf
+
------------------------ k
2
1.45
3.7
---------- 0.035hr
1
0.014 = hr
1
= =
K1 0.53hr
1
= k
m
kf +
K2 0.035hr
1
= Cp
m
k
mu
k
mf
+
Cp
0 ( )
50ng mL =
ng mL
dX
u
dt
---------
k
f
X
0
0.03 5 ( ) 0.15ng mL = =
T
mid Time T
X
u
X
u
X
u
T
----------
X
u
T
----------
0.41 1
0.24 1
0.15 1
0.08 1
0.08 2
hr
1
hr
1
27 0.53
28 0.53
29
30
31
32
33 94
34
35
36
37 174
38 16000
39 94
40 174
41 1.9
42 528
43 16000
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
hr
1
hr
1
50 29 + ( )
2
----------------------- 1 39.5ng mL hr =
0 7.5 + ( )
2
--------------------- 1 3.75ng mL hr =
2
0.53
---------- 3.77ng mL hr =
3.4
0.035
------------- 97ng mL hr =
ng mL hr
19.8
1
0.035
-------------
1
0.53
----------
,
_
528ng mL hr =
AUC
dX
u
dt
---------
,
_
vsT 1mg =
AUC
dX
mu
dt
-------------
,
_
vsT 2.25mg =
ng mL hr
2
ng mL hr
2
ng mL hr
ng mL hr
2
hr
ng mL hr
ng mL hr
2

16000
528
--------------- 30.3hr =
X
0
5mg =
X
u 0 ( )
0 =
X
f 0 ( )
0 =
X
m 0 ( )
0 =
X
mu 0 ( )
0 =
X
mf 0 ( )
0 =
X
0 =
X
u
1mg =
X
f
0.3mg = 5 1 2.25 1.45 ( ) =

X
m
0 =
X
mu
2.25mg =
X
mf
1.45mg =
Cp
0
50ng mL =
Cp
m 0 ( )
19.8ng mL =
Vd
dose
Cp
0 ( )
------------- 100L = =
Vd
m
k
m
X
0
( )
K1 K2 ( ) I
---------------------------
0.39 5 ( )
K1 K2 ( ) 0.0198 ( )
-------------------------------------------------------------- 200 = =
Practice Exams: Section 1 : Ciprofloxacin Section 1
14.3 Ciprofloxacin Section 1
14.3.1 CIPROFLOXACIN DATA
Ciprofloxacin (Cipro ) is a fluoroquinolone, synthetic broad spectrum antibacterial agent. It is reasonably well
absorbed orally and is excreted into the urine and is metabolized to four known metabolites which are also excreted
into the urine. Before an accurate analytical assay was worked out for ciprofloxacin, a microbiological assay was used
to determine the pharmacokinetics. This assay utilized the ability of ciprofloxacin to kill microorganisms grown on an
agar plate and create a clear zone of no growth, the zone of inhibition. The following data was collected from that pro-
cedure: (Intercept for the extrapolated metabolite graph was 0.372 mg/L)
Data Set 0ne Data Set Two
Zone -mm Time (hrs)
zone - mm Concentration Spiked plasma
27 1 4.7 0.01
23.2 5 13.5 0.05
20.4 8 17.3 0.1
18.5 10 19.5 0.15
5.2 24 21 0.2
23.5 0.3
28 0.7
PROBLEM TABLE 11 - 1. Data from 500 mg IV Bolus Cipro.
Time
(Hrs)
Cp
(mg/L)
Cpm
(mg/L)
Interval
(hours)
Cipro (mg)
in urine
0.5 0.045 0 - 4 184
1 3 0.077 4 - 8 92
2 2.53 0.115 8 - 12 46
3 2.12 0.129
4 1.79 0.128
5 0.119
6 1.26 0.108
8 0.893 0.084
10 0.062
12 0.045
16 0.023
18 0.016
20 0.012
14.3.2 CIPROFLOXACIN QUESTIONS
From the above information find the pharmacokinetic parameters:
1) K (elimination rate constant of Cipro) (hr
-1
)
2) kr (urinary excretion rate constant of Cipro)(hr
-1
)
3) km (metabolism rate constant of Cipro)(hr
-1
)
4) kmu (urinary excretion rate constant of the metabolites)(hr
-1
)
5) Cp0 (IV bolus Cipro) (mic/mL)
6) Vd (Cipro)(L.)
7) Vdm (metabolites)(L.)
8) AUC (Cp vs t for Cipro by IV bolus) (mic/mL * hr)
9) AUMC (t*Cp vs t for Cipro by IV bolus (mic/mL * hr
2
)
10) MRT (Cipro)(hr)
11) AUC (dXu/dt vs t(mid) for Cipro by IV bolus) (mg)
12) X
inf
(Cipro in the body at infinite time)
13) X
u
inf (Cipro in the urine at infinite time)
14) X
m
inf (metabolites in the body at infinite time)
15) X
mu
inf (metabolites in the urine at infinite time)
16) T
1/2
(Cipro)(hr)
17) Clearance (Cipro)(L/hr)
18) dR/dT (mm/hr)
19) dR/d(lnC) (mm)
20) d(lnC)/dt (Cipro)(hr-1)
21 Slope of Cp vs T ([Cipro] vs t) on semi-log paper
22 Slope of dXu/dt vs T(mid) vs t on semi-Log paper
23 Slope of terminal portion of Cpm vs T on semi-log paper
24) Slope of stripped portion of Cpm vs T on semi-log paper
25) Equation for the rate of formation of the metabolites in the urine (dX
mu
/dT vs T)
a) kmu * Xo * (e
-Kt
- e
-kmut
) / (kmu - K)
b) kmu * km * Xo * (e
-Kt
- e
-kmut
) / (K - kmu)
c) km * Xo * (e
-Kt
- e
-kmut
) / (kmu - K)
d) kmu * km * Xo * {(1-e
-Kt
)/K- (1-e
-kmut
)/kmu} / (kmu - K)
e) kmu * km * Xo * (e
-Kt
- e
-kmut
) / (kmu - K)
14.3.3 CIPROFLOXACIN SOLUTIONS
Ciprofloxacin Model
X
Xm
Xu
Xmu
km
ku
kmu
10
-2
10
-1
10
0
Concentration (mic/mL)
0
5
10
15
20
25
30
R
e
s
p
o
n
s
e

(
z
o
n
e

-

m
m
)

Ciprofloxacin
0 5 10 15 20 25
Time (hr)
0
5
10
15
20
25
30
R
e
s
p
o
n
s
e

(
z
o
n
e

-

m
m
)

Ciprofloxacin
0 2 4 6 8 10
Tmid (hours)
10
1
10
2
d
X
u
/
d
t

(
m
g
)

Ciprofloxacin Urine data
0 5 10 15 20
Time (hours)
10
-2
10
-1
10
0
C
o
n
c
e
n
t
r
a
t
i
o
n

(
m
i
c
.
m
L
)

Ciprofloxacin Metabolite data
0 2 4 6 8
Time (hours)
10
-1
10
0
10
1
C
o
n
c
e
n
t
r
a
t
i
o
n

(
m
i
c
/
m
L
)

Ciprofloxacin
1.
2.
3
4
5
6
7
8
Cp vs T
9.
10
11
12
13
14
15
16
17
18
19
20
21 Slope of Cp vs T =
22 Slope of
23 Slope of terminal portion of
24 Slope of stripped portion of
25
K 0.173hr
1
=
k
r
R
0
X
0
------
65.13mg hr
500mg
------------------------------- 0.13hr
1
= = =
k
m
0.043hr
1
=
k
mu
0.462hr
1
=
Cp
0
3.57mic mL =
Vd 140L =
Vd
m
200L =
AUC 20.7mic mL hr =
AUMC 119.7mic mL hr
2
=
MRT 5.8hr =
AUC 375mg =
dX
u
dt
---------vs t
mid
( )
X
0 =
X
u
375mg =
X
m
0 =
X
mu
125mg =
T
1 2
4.0hr =
Cl 24.2L hr =
dR
dT
------- 0.95mm hr =
dR
d C ln ( )
----------------- 5.5mm =
d C ln ( )
dt
----------------- 0.173hr
1
=
0.173
dX
u
dt
---------vs t
mid
( ) 0.173 =
Cp
m
vsT 0.173 =
Cp
m
vsT 0.462 =
k
mu
k
m
X
0

k
mu
K ( )
----------------------------- e
Kt
e
kmut
( )
Practice Exams: Section 1 : Methylphenidate Section 1
14.4 Methylphenidate Section 1
Citation
14.4.1 METHYLPHENIDATE DATA
Methylphenidate (MP) (Ritalin) is an effective stimulant in the treatment of narcolepsy in adults and attention deficit
syndrome in children. It is entirely metabolized to the inactive metabolite, Ritalinic Acid (RA), by the liver which is
subsequently excreted unchanged into the urine. Pharmacological response was measured objectively using sleep
latency as measured by encephalography. Sleep latency is the time required to fall asleep in a darkened quiet room.
Pharmacological Response Data
Time (hr) Response (min) Cp (mcg/mL) Response (min)
0.5 22 6 22.5
1 16 5 18
1.5 10 4 15
2 5 3 10
PROBLEM TABLE 11 - 1. Plasma Profiles
(Intercept of extrapolated RA line 0.21
mic/mL)
Plasma Vs. Time Profile
10 mg MP given by IV Bolus
Time (hr)
Cp (MP)
(mcg/mL)
Cpm (RA)
(mcg/mL
0.5 0.091 0.022
1 0.067 0.029
1.5 0.049 0.030
2 0.035 0.028
2.5 0.026 0.024
3 0.019 0.020
4 0.010 0.012
6 0.003 0.004
8 ------- 0.0013
14.4.2 METHYLPHENIDATE QUESTIONS:
From the above information find the phar-
macokinetic parameters:
1) K (elimination rate constant of MP) (hr
-1

)
2) kr (urinary excretion rate constant of
MP)(hr
-1
)
3) km (metabolism rate constant of
MP)(hr
-1
)
4) kmu (urinary excretion rate constant of
(RA)(hr
-1
)
5) Cp0 (IV bolus MP) (mic/mL)
6) Vd (MP)(L.)
7) Vdm (RA)(L.)
8) AUC (Cp vs t for MP by IV bolus) (mic/
mL * hr)
9) AUMC (t*Cp vs t for MP by IV bolus
(mic/mL * hr
2
)
10) MRT (MP)(hr)
11) AUC (dXu/dt vs t(mid) for MP by IV
bolus) (mg)
12) AUC (dXmu vs t(mid) for RA)(mg)
13) X
0
(MP in the body at zero time)
14) X
m0
(RA in the body at zero time)
15) X
mu0
(RA in the urine at zero time)
16) X
1hr
(MP in the body at 1 hr.)
17) X
m1hr
(RA in the body at 1 hr)
18) X
inf
(MP in the body at infinite time)
19) X
u
inf (MP in the urine at infinite time)
20) X
m
inf (RA in the body at infinite time)
21) T
1/2
(MP)(hr)
22) Clearance (MP)(L/hr)
23) dR/dT (min/hr)
24) dR/d(lnCp) (%)
25) d(lnCp)/dt (MP)(hr-1)
26) The slope of Cp vs T ([MP] vs t) on
semi-log paper
27) The equation for Cp vs T ([MP] vs t)
on semi- log paper
28) The slope of terminal portion of
dXmu/dt vs T(mid) on semi-Log paper
29) The equation for dXmu/dt vs T(mid)
on semi- log paper
30) The slope of terminal portion of Cp
m
vs
T ([RA] vs t) on semi-log paper
31) The equation for Cpm vs T ([RA] vs t)
on semi- log paper
32) The slope of stripped portion of Cp
m
vs
T ([RA] vs t) on semi-log paper
33) The equation for X
m
(bar) (Laplace domain
equation for RA in the body)
34) The equation for X
m
(RA in the body)
14.4.3 METHYLPHENIDATE SOLUTIONS
X
Xm

Xmu
km
kmu
0.5 1.0 1.5 2.0
Time (hr)
0
5
10
15
20
25
R
e
s
p
o
n
s
e

(
m
i
n
)

Methyl Phenidate
R vs C
Concentration
R
e
s
p
o
n
s
e
10
0
10
1
8
10
12
14
16
18
20
22
24
0 2 4 6 8
Time (hours)
10
-2
10
-1
10
0
C
o
n
c
e
n
t
r
a
t
i
o
n

(
m
i
c
/
m
L
)

MP IV Bolus - Metab
0 1 2 3 4
Time (hours)
10
-2
10
-1
10
0
C
o
n
c
e
n
t
r
a
t
i
o
n

(
m
i
c
/
m
L
)

Methyl Phenidate IV Bolus
1
2
3
4
5
6 (change in answer
pool)
7 (change in answer
pool)
8
9.
10
11 MP is not excreted in
the urine
12 All of RA is
excreted in the urine
13
14
15
16 (change in answer
pool)
17 (change in answer
pool)
18
19
20
21
22
23
24 min
25
26 The slope of Cp vs T
27 The equation for Cp vsT

28 The slope of terminal portion of
29 The equation for
30 the slope of the terminal portion of
31 The equation for
32 The slope of stripped portion
33
34 The equation for
K 0.63hr
1
=
k
r
0 =
k
m
0.63hr
1
=
k
mu
0.90hr
1
=
Cp
0
0.125mic mL =
Vd 80L =
Vd
m
115L =
AUC 0.20mic mL hr =
AUMC 0.315mic mL hr
2
=
MRT 1.57hr =
AUC 0 =
AUC 10mg =
X
0
10mg =
X
m o ( )
0 =
X
mu 0 ( )
0 =
X
1hr
5.3 =
X
m1hr
2.8 =
X
0 =
X
u
0 =
X
m
0 =
T
1 2
1.1hr =
Cl 50.4L hr =
dR
dT
------- 11.4min hr =
dR
d Cp ln ( )
--------------------- 17.5 =
d Cp ln ( )
dT
--------------------- 0.63hr
1
=
0.63hr
1
Cp Cp
0
e
k t
=
dX
mu
dT
-------------vsT
mid
0.63 =
dX
mu
dT
-------------vsT
mid
k
mu
k
m
X
0

K2 K1 ( )
----------------------------- e
K1t
e ( ) =
Cp
m
vsT RA ( )vsT 0.94 =
Cp
m
vsT RA ( )
k
m
X
0
K2 K1 ( )
------------------------- e
K1t
e ( ) =
0.79
X
m
k
m
X
0
s K1 + ( ) s K2 + ( )
---------------------------------------------- =
X
m
k
m
X
0
K2 K1 ( )
------------------------- e
K1t
e
K 2t
( ) =
Practice Exams: Section 1 : Adinazolam - Section 1
14.5 Adinazolam - Section 1
Fleishaker [Pharm Res 8 (2): 162-7(1991),Pharm Res 6 (5): 379-86(1989),Psychopharm 99:34-9(1989),Psychopharm 105:181-
5(1991)];Kroboth [J Clin Pharmacol 31:580-6(1991)]; Wagner [Biopharm Drug Dis 8:405-25(1987)].
14.5.1 ADINAZOLAM DATA
Adinazolam (AD) is a triazolobenzodiazepine prodrug which has been shown to have antidepressant activity through
its metabolite, N-desmethyladinazolam (NDMAD). Both AD and NDMAD are excreted into the urine. The following
data regarding AD and NDMAD was collected from the works cited. AD appears to interfere with mental ability. One
of the tests was the ability to Substitute Digits for Symbols (DSST) and the interference of that process was the
response measured below:
From the above information find the pharmacokinetic parameters:
PROBLEM TABLE 11 - 1. Pharmacological Response
% Pharm Response Time (hrs) % Pharm Response NDMADC Conc (ng/,L)
59.7 2 33 200
45.3 4 48 300
29.5 6 59 400
15.5 8 68 500
0 12 74 600
PROBLEM TABLE 11 - 1. Five mg IV bolus dose of AD yieled: (intercept of extrapolated metabolite line is 150 ng/mL)
Plasma Data Urine Data
Time
(hr)
Cp (AD)
(ng/mL)
Cpm(NDMAD)
(ng/mL)
Time (mid)
AD Ecretion Rate
(mg/hr)
0.5 47 0.5 0.56
1 40 15.4 1 0.48
2 28 23.5 2 0.34
3 27.3 4 0.18
4 14.7 28 6 0.09
5 27
6 7.5 24.9
8 20
10 15
12 11
15 7.5
18 4.2
20 2.8
22 1.9
24 1.2
t
14.5.2 ADINAZOLAM QUESTIONS
1) K (elimination rate constant of AD) (hr
-1
)
2) kr (urinary excretion rate constant of AD)(hr
-1
)
3) km (metabolism rate constant of AD)(hr
-1
)
4) kmu (urinary excretion rate constant of NDMAD)(hr
-1
)
5) Cp0 (IV bolus AD) (ng/mL)
6) Vd (AD)(L.)
7) Vdm (NDMAD)(L.)
8) AUC (Cp vs t for AD by IV bolus) (ng/mL * hr)
9) AUMC (t*Cp vs t for AD by IV bolus (ng/mL * hr
2
)
10) MRT (AD)(hr)
11) AUC (dXu/dt vs t(mid) for AD by IV bolus) (mg)
12) X
inf
(AD in the body at infinite time)
13) X
u
inf (AD in the urine at infinite time)
14) X
m
inf (NDMAD in the body at infinite time)
15) X
mu
inf (NDMAD in the urine at infinite time)
16) T
1/2
(AD)(hr)
17) Clearance (AD)(L/hr)
18) dR/dT (%/hr)
19) dR/d(lnC) (%)
20) d(lnC)/dt (NDMAD)(hr-1)
21 Slope of Cp vs T ([AD] vs t) on semi-log paper
22 Slope of dXu/dt vs T(mid) vs t on semi-Log paper
23 Slope of terminal portion of Cpm vs T ([NDMAD] vs t) on semi-log paper
24) Slope of stripped portion of Cpm vs T ([NDMAD] vs t) on semi-log paper
25) X
m
(bar) (Laplace domain equation for NDMAD in the body)
PROBLEM TABLE 11 - 1. Answer Pool
Numbers LaPlace Forms
a -1.33 -0.1 0 1 10 100 Xo/(s+K)
b -1.55 -0.133 0.1 1.33 12.5 120 Xo/(s+km)
c -2 -0.15 0.133 1.5 20 167 Xo/(s+kmu)
d -3.33 -0.2 0.15 2 30 200 km * Xo / ((s+km) * (s+kmu))
e -4 -0.333 0.2 3 37.5 375 kmu * Xo / ((s+km) * (s+kmu))
f -5 -0.5 0.333 4 40 425 km * Xo / ((s+km) * (s+K ))
g -6.93 -0.693 0.5 5 50 500 kmu * Xo / ((s+K ) * (s+kmu))
h -7.5 -0.73 0.693 6 55.6 630 km * Xo / ((s+K ) * (s+kmu))
i -8.25 -0.85 0.75 6.67 66.7 775 kmu*km*Xo / ((s+K ) * (s+kmu))
j -9 -0.95 0.84 7.5 75 930 kr*Xo / ((s+K ) * (s+kmu))
14.5.3 ADINAZOLAM SOLUTIONS
X
Xm
Xu
Xmu
km
ku
kmu
10
2
10
3
Concentration (ng.mL)
30
40
50
60
70
80
R
e
s
p
o
n
s
e

(
%
P
-
c
o
l
)

Adinazolam metabolite
R vs T
Time (hr)
2 3 4 5 6 7 8
10
20
30
40
50
60
o
n
s
e

%
0 1 2 3 4 5 6
Time (hours)
10
0
10
1
10
2
C
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
L
)

Adinazolam IV Bolus
0 5 10 15 20 25
Time (hours)
10
0
10
1
10
2
C
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
L
)

AD IV Bolus - Metab
1
2
3
4
5
6.
7
8
9
10
11
12
13
14
15
16
17
18 %hr
19 %
20
21 Slope of Cp vs T([AD] vs t) = -
0.333
22 Slope of
23 Slope of the terminal portion of
24 Slope of the stripped portion = -
0.333
25
K 0.333hr
1
=
k
r
0.133hr
1
=
k
m
0.2hr
1
=
k
mu
0.2hr
1
=
Cp
0
55.6ng mL =
Vd 90L =
Vd
m
50L =
AUC 167ng mL hr =
AUMC 500ng mL hr
2
=
MRT 3.0hr =
AUC
m
2.0mg =
X
0 =
X
u
2.0mg =
X
m
0 =
X
mu
3.0mg =
T
1 2
2hr =
Cl 30L hr =
dR
dT
------- 7.42 =
dR
d C ln ( )
----------------- 37.5 =
d C ln ( )
dt
----------------- 0.2hr
1
=
dX
u
dt
---------vsT
mid ( )
0.333 =
Cp
m
vsT 0.2 =
X
m
k
m
X
0
s K + ( ) s k
mu
+ ( )
---------------------------------------- =
Practice Exams: Section 1 : Labetalol - Section 1
14.6 Labetalol - Section 1
Saotome, et. al (J. Clin. Pcol 1993,33:979- 988)
14.6.1 LABETALOL DATA
Labetalol is a selective - blocking and nonselective -blocking agent used in the treatment of hypertension. It is
excreted unchanged into the urine and extensively metabolized. The metabolites are excreted into the urine and bile.
Labetalol reduces diastolic blood presure.
PROBLEM TABLE 11 - 1. P-col Resp vs Time (hrs) P-col Resp v Labetalol Conc
Pharmacological Response Profiles
Decrease in BP
(mm Hg)
Time
(hr)
Decrease in BP
(mm Hg)
Cp
(ng/mL)
22.2 2 14.5 100
20.3 4 16.5 160
18.5 6 19.5 275
16.6 8 22.5 525
PROBLEM TABLE 11 - 1. Data from a 200 mg IV Bolus dose (Intercept of extrapolated Metabolite data = 22.7 mg/hr)
Time
(hrs) Cp
Time
(mid)
Labetalol
Excretion rate
(mg/hr)
Metabolite
Excretion Rate
(mg/hr)
0.5 364 0.5 1.82 5.1
1 331 1 1.66 8.2
2 274 1.5 9.8
4 187 2 1.37 10.6
6 128 2.5 10.7
8 88 3 10.5
4 0.94 9.5
6 0.64 7.0
8 4.9
12 2.3
18 0.74
24 0.24
t
14.6.2 LABETALOL QUESTIONS
From the above information find the phar-
macokinetic parameters:
1) K (elimination rate constant of labe-
talol) (hr
-1
)
2) K2 (elimination rate constant of labe-
talol metabolites (hr
-1
)
3) kr (urinary excretion rate constant of
labetalol)(hr
-1
)
4) km (metabolism rate constant of labe-
talol)(hr
-1
)
5) kmu (urinary excretion rate constant of
Metabolites of labetalol)(hr
-1
)
6) kmb (biliary excretion rate constant of
Metabolites of labetalol)(hr
-1
)
7) Cp0 (IV bolus labetalol) (ng/mL)
8) Vd (labetalol)(L.)
9) AUC (Cp vs t for labetalol by IV bolus)
(ng/mL * hr)
10) AUMC (t*Cp vs t for labetalol by IV
bolus (ng/mL * hr
2
)
11) MRT (labetalol)(hr)
12) AUC (dXu/dt vs t(mid) for labetalol by
IV bolus) (mg)
13) AUC (dXmu/dt vs t(mid) for Metabo-
lites (mg))
14) AUC (dXmb/dt vs t(mid) for Metabo-
lites (mg))
15) X
inf
(labetalol in the body at infinite time (mg))
16) X
u
inf (labetalol in the urine at infinite time (mg))
17) X
m
inf (Metabolites of labetalol in the body at infi-
nite time (mg))
18) X
mu
inf (Metabolites of labetalol in the urine at infi-
nite time (mg))
19) X
mb
inf (Metabolites of labetalol in the bile at infi-
nite time (mg))
20) T
1/2
(labetalol)(hr)
21) Clearance (labetalol)(L/hr)
22) dR/dT (%/hr)
23) dR/d(lnC) (%)
24) d(lnC)/dt (labetalol)(hr-1)
25 Slope of Cp vs T ([labetalol] vs t) on
semi-log paper
26 Slope of dXu/dt vs T(mid) vs t on
semi-Log paper
27 Slope of terminal portion of Cpm vs T
([Metabolites of labetalol] vs t) on
semi-log paper
28) Slope of stripped portion of Cpm vs T
([Metabolites of labetalol] vs t) on
semi-log paper
29) X
m
(bar) (Laplace domain equation for Metabolites
of labetalol in the body)
30) dXmu / dT (equation for the rate of
excretion of metabolites into the urine)
31) Fraction of labetalol excreted
unchanged.
32) Fraction of labetalol eliminated as
metabolites in the urine.
33) Fraction of labetalol eliminated as
metabolites in the bile.
14.6.3 LABETALOL SOLUTIONS
X
Xm Xmf
Xu
Xmu
km
ku
kmu kmf
2 3 4 5 6 7 8
Time (hr)
16
17
18
19
20
21
22
23
R
e
s
p
o
n
s
e

(
m
m
H
g
)

Labatalol
10
2
10
3
Concentration (ng.mL)
14
16
18
20
22
24
R
e
s
p
o
n
s
e

(
m
m
H
g
)

Labatalol
0 2 4 6 8
Time (hours)
Labatalol
10
1
10
2
10
3
C
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
L
)

0 1 2 3 4 5 6
Tmid (hours)
Labatalol
10
-1
10
0
10
1
E
x
c
r
e
t
i
o
n

r
a
t
e

(
m
g
/
h
r
)

0 5 10 15 20 25
Time (hours)
10
-1
10
0
10
1
10
2
E
x
c
r
e
t
i
o
n

R
a
t
e

(
m
g
/
h
r
)

Labatalol Metabolite
1
2.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22 %hr
23 %
24
25 Slope of Cp vs T =
26 Slope of

27 Slope of terminal portion
of
28 Slope of stripped portion of
29
30
31 Fraction of labetalol excreted
unchanged: %
32 Fraction of labetalol excreted as
metabolites in urine:
%
33 Fraction of labetalol eliminated as
metabolites in bile:
%
K1 0.190hr
1
=
K2 0.792hr
1
=
k
r
0.01hr
1
=
k
m
0.18hr
1
=
k
mu
0.38hr
1
=
k
mb
0.41hr
1
=
Cp
0
400ng mL =
Vd 500L =
AUC 2105ng mL hr =
AUMC 11072ng mL hr
2
=
MRT 5.26hr =
AUC 10.5mg =
AUC 91.2mg =
AUC 98.3mg =
X
0 =
X
u
10.5mg =
X
m
0 =
X
mu
91.2mg =
X
mb
98.3mg =
T
1 2
3.64hr =
Cl 95L =
dR
dT
------- 0.93 =
dR
d C ln ( )
----------------- 4.90 =
d C ln ( )
dt
----------------- 0.190hr
1
=
0.190hr
1
dX
u
dt
---------vsT
mid ( )
vs t ( ) 0.190 =
Cp
m
vsT 0.190 =
Cp
m
vsT 0.79 =
X
m
k
m
X
0
s K1 + ( ) s K2 + ( )
------------------------------------------ =
X
mu
dt
---------
k
mu
k
m
X
0
( )
K1 K2 ( )
---------------------------------- e
K2t
e
K1T
( ) =
10.5
200
---------- 100 5.25 =
91.2
200
---------- 100 45.6 =
98.3
200
---------- 100 49.15 =
Practice Exams: Section 1 : Zidovudine Section 1
14.7 Zidovudine Section 1
14.7.1 ZIDOVUDINE DATA
Zidovudine (ZDV - formerly azidithymidine (AZT)) is used to treat HIV positive patients with AIDS and AIDS related
complex (ARC). The in vitro virustatic concentration is 250 mic/mL. While the pharmacokinetics of ZDV is complex,
we can approximate it with the following model. ZDV is excreted unchanged into the urine to UZDV. It is metabo-
lized by hepatic glucuronidation to an inactive metabolite, GZDV, and also metabolized by intracellular phosphoryla-
tion to the active metabolite, ZDV-TP. Both metabolites are excreted into the urine (UGZDV and UZDV-TP). The
anti-retroviral activity was shown in the following data:
PROBLEM TABLE 11 - 1. ZDV-TP Response vs time and response vs concentration data
Pharmacological Response Data
Concentration
ZDV-TP (ng/mL)
Activity
%
Time
(min)
Activity
%
100 80 0 100
90 76.8 30 100
75 68.5 60 100
50 52.3 120 92
25 24.5 240 82
360 72
480 62
PROBLEM TABLE 11 - 1. 100 mg dose ZDV given by IV Bolus to 70 KG patient
Time
(hours)
Cp ZDV
(ng/mL)
Cpm GZDV
(ng/mL)
Interval
(hrs)
UZDV Collected
(mg)
Rate of
excretion data
AUC
UGZDV (mg)
0.25 40 0 - 1 9.2 60
0.5 75 1 - 2 4.8
0.75 100 2 - 3 2.5
1 315 125 4 - 6 1
1.5 150
2 170 160
3 91 160
4 48 145
6 13 100
8 65
10 40
12 25
Please use the following nomenclature:
D = Dose of ZDV
K = elimination rate constant of ZDV
kr = excretion rate constant of ZDV
kmu1 = excretion rate constant of ZDV-TP
kmu2 = excretion rate constant of GZDV
km1 = metabolism rate constant of ZDV to ZDV-TP
km2 = metabolism rate constant of ZDV to GZDV
14.7.2 ZIDOVUDINE QUESTIONS
1) Using Laplace transforms, find the
equation for the rate of excretion of GZDV
into the urine. (For this question use the
following answer set:
a = I only
b = III only
c = I + II only
d = II + III only
e = All three
I (kmu2*km2*D/(K-kmu2))*(exp(-K*t))
II (kmu2*km2*D/(K-kmu2))*(exp(-
kmu2*t))
III -(kmu2*km2*D/(K-kmu2))*(exp(-
K*t))
2) Using linear regression on the pharma-
cological response / concentration profile,
what was the Summation of XY?
3) What is d%R/d(lnC)(%)?
4) What is d%R/dt (%/hr)?
5) What is K (hr^-1)?
6) What is kr (hr^-1)?
7) What is km1 (hr^-1)?
8) What is km2 (hr^-1)?
9) What is kmu1 (hr^-1)?
10) What is kmu2 (hr^-1)?
11) What is the terminal slope (*-1) of
ln(ZDV) vs t (hr^-1)?
ln(ZDV-TP) vs t (hr^-1)?
ln(ZDV-TP) vs t (hr^-1)?
ln(GZDV) vs t (hr^-1)?
ln(dUZDV/dt) vs t (hr^-1)?
16) What is the intercept of ZDV vs t (ng/
mL)?
17) What is the intercept of dUZDV/dt vs t
(mg/hr)?
18) What is the intercept of the extrapo-
lated line from plasma GZDV vs time data
(ng/mL)?
19) What is the intercept of the extrapo-
lated line from dUGZDV/dt vs time data
(mg/hr)?
20) What is the Cp0 of ZDV (ng/mL)?
21) What is the volume of distribution of
ZDV (L)?
22) What is the volume of distribution of
GZDV (L)?
23) What is the clearance of ZDV (L/hr)?
24) What is the half life of ZDV (hr)?
25) What is the MRT of ZDV (hr^-1)?
26) What is the AUC of the first trapazoid
of ZDV vs time (ng/mL*hr)?
27) What is the AUC(from 0 to infinity) of
the IV bolus ZDV plasma data (ng/
mL*hr)?
28) How much ZDV is in the body at infi-
nite time (mg)?
29) How much GZDV is in the body at
infinite time (mg)?
30) How much ZDV-TP is in the body at
infinite time (mg)?
31) How much ZDV is in the urine
(UZDV) at infinite time (mg)?
32) How much GZDV is in the urine
(UGZDV) at infinite time (mg)?
33) How much ZDV-TP is in the urine
(UZDV-TP) at infinite time (mg)?
14.7.3 ZIDOVULDINE SOLUTIONS
X
Xm2
Xm1
Xmu1
Xu
Xmu2
km2
ku
kmu2
km1
kmu1
0 100 200 300 400 500
Time (min)
60
70
80
90
100
110
R
e
s
p
o
n
s
e

(
%

A
c
t
i
v
i
t
y
)

Zidovudine
10
1
10
2
Concentration (ng/mL)
20
30
40
50
60
70
80
90
R
e
s
p
o
n
s
e

(
%

A
c
t
i
v
i
t
y
)

Zidovudine
0 1 2 3 4 5 6
Time (hours)
10
1
10
2
10
3
C
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
L
)

Zidovudine
0 2 4 6 8 10 12
Time (hours)
10
1
10
2
10
3
C
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
L
)

Zidovudine Metobolite
0 1 2 3 4 5
Tmid (hours)
10
-1
10
0
10
1
10
2
U
Z
V
D

(
m
g
)

Zidovudine Urine data
1. Answer is D - II and III
2 1289.2
3 40%
4 -0.08333%hr
5
6
7
8
9
10
11
12
13 Skip - same question as #12
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28 0
29 0
30 0
31
32
33
K 0.630hr
1
=
k
r
0.125hr
1
=
k
m1
0.25hr
1
=
k
m2
0.25hr
1
=
k
mu1
0.125hr
1
=
k
mu2
0.378hr
1
=
0.630hr
1
0.250hr
1
0.25hr
1
0.630hr
1
600ng mL
12.6mg hr
500ng mL
12.6mg hr
600ng mL
166.7L
200L
105L hr
1.1hr
1.6hr
457.5ng mL hr
952ng mL hr
20mg
60mg
20mg
Practice Exams: Section 1 : Fosinopril Section 1
14.8 Fosinopril Section 1
Kostis et al Fosinopril: Pharmacokinetics and pharmacodynamics in congestive heart failure Clin Pcol Ther 58(6) 660-5
(1995); Hui et al Pharmacokinetics of fosinopril in patients with various degrees of renal function Clin Pcol Ther 49(4) 457 -66
(1991)
14.8.1 FOSINOPRIL DATA
Fosinopril Sodium is a phosphinic prodrug of the angiotensin converting enzyme (ACE) inhibitor fosinoprilat effective
in the treatment of hypertension and chronic heart failure (CHF). The parent compound is weakly active, if at all. Its
sole metabolite, fosinoprilat, exhibits almost all of the pharmacological activity. After administration, fosinopril is
entirely converted to the active fosinoprolat by esterases in the liver. Unlike other ACE inhibitors, elimination of fos-
inoprilat is divided equally between renal and hepatic pathways (liver metabolism). The following information was
obtained from a 70 Kg male.
Wherever necessary, please use the following symbols:
Cp = plasma concentration of parent drug, fosinopril
Cpm1 = plasma concentration of metabolite, fosinoprilat.
Cpm2= plasma concentration of metabolite of fosinoplilat.
X = amount of parent compound, fosinopril, in the body
Xm1 = amount of metabolite, fosinoprilat, in the body
Xm2 = amount of metabolite of fosinoprilat in the body
Xu = cumulative amount of parent drug in urine.
Xmu1 = cumulative amount of metabolite, fosinoprilat, in urine.
Xmu2 = cumulative amount of metabolite of fosinoprilat in urine.
ku = renal excretion rate constant of parent drug in plasma.
kmu1 = renal excretion rate constant for metabolite, fosinopril, in plasma.
kmu2 = renal excretion rate constant for metabolite of fosinopril in plasma.
kf = fecal excretion rate constant of parent drug in plasma.
kmf1 = fecal excretion rate constant for metabolite, fosinopril, in plasma.
kmf2 = fecal excretion rate constant for metabolite of fosinopril in plasma.
km1 = metabolism rate constant of fosinopril in plasma.
km2 = metabolism rate constant of fosinoprilat in plasma.
K1 = elimination rate constant of parent drug in plasma = summation of all processes which remove fosinopril.
K2 = elimination rate constant of metabolite1 in plasma = summation of all processes which remove fosinoprilat.
K3 = elimination rate constant of metabolite2 in plasma = summation of all processes which remove the metabolite of fosinoprilat.
PROBLEM TABLE 11 - 1. Pharmacological Response data (Six hours after dosing with fosinopril)
Time
(hr)
Fall in SSBP
(mm Hg)
Fall in SSBP
(mg Hg)
Dose
(mg)
3 22 5 10
5 21 11 20
8 19 16 40
11 17 22 80
13 16
Plasma Data
(from7.5 mg Fosinoprilat IV Bolus)
Urine Data
(from 20 mg Fosinopril IV bolus)
(Intercept 0.855 mg/hr)
Tme
(hours)
Cp
(Fosinoprilat)
(ng/mL)
Interval
(hr)
Amount (Fosinoprilat)
(mg)
1 387 0 - 1 0.158
2 360 1 - 2 0.362
3 335 2 - 3 0.467
4 311 3 - 4 0.513
6 269 4 - 6 1.05
6 - 10 1.84
10 - 14 1.42
14 - 22 1.84
22 - 26 0.592
14.8.2 FOSINOPRIL QUESTIONS
From the parent compound, Fosinopril,
given by IV bolus, find the equation for:
1) X, the mass of parent drug, Fosinopril,
in the body
) Xu, the mass of parent drug, Fosinopril,
in urine.
3) dXu/dt, the rate of excretion of parent
drug, Fosinopril, in urine.
4) Xf, the mass of parent drug, Fosino-
pril, in feces.
5) Xm1, the mass of metabolite, Fosino-
prilat, in the body
6) Xm1u, the mass of metabolite, Fosi-
noprilat, in urine.
7) dXm1u/dt, the rate of excretion of
metabolite, Fosinoprilat, in urine.
8) Xm1f, the mass of metabolite, Fosino-
prilat, in feces.
9) Cp, the plasma concentration of parent
drug, Fosinopril
10) Cpm1, the plasma concentration of
metabolite, Fosinoprilat.
Find the value of:
11) dR/dT
12) dR/d(ln(Cpm1))
13) d(ln(Cpm1))/dT
14) k
u
, the renal excretion rate constant of parent drug,
Fosinopril, in plasma.
15) k
m1
, the metabolism rate constant of parent drug,
Fosinopril, in plasma.
16) k
mu1
, the renal excretion rate constant for metabo-
lite, Fosinoprilat, in plasma.
17) k
m2
, the metabolism rate constant for the metabo-
lite of Fosinoprilat in plasma.
18) K
1
, the elimination rate constant of parent drug in
plasma , the summation of all processes which remove
Fosinopril.
19) K
2
, the elimination rate constant of metabolite in
plasma , the summation of all processes which remove
Fosinoprilat.
For fosinoprilat IV, find the value of :
20) AUC
(fosinoprilat)
21) AUMC
(fosinoprilat)
22) MRT(fosinoprilat)
23) Ke for fosinoprilat (hr
-1
)
24) for Fosinoprilat (hr)
25) Cp
0(fosinoprilat)
for iv dose (ng/mL)
26) Vd for Fosinoprilat (L)
27) Cp of Fosinoprilat at eight hours
after the IV dose
For fosinoprilat given as IV fosinopril,
dXm1/dt, find the value of :
28) AUC
(fosinoprilat)
(mg)
29) AUMC
(fosinoprilat)
30) MRT
(fosinoprilat)
31) K2 for fosinoprilat (hr
-1
)
32) T
?
for Fosinoprilat (hr)
33) K1 for fosinopril (hr
-1
)
T
1 2
PROBLEM TABLE 11 - 1. Answer Pool
Minus Small Med. Large Equations More equations
A -0.037 0 1.35 155 None
((k
m1
X
0
/V
dm
)/(K1-K2))(e
-K2t
-e
-K1t
)
B -0.050 0.037 5.0 232
X
0
e
-K1t
((k
m1
X
0
/V
dm
)/(K1-K2))(e
-K1t
-e
-K2t
)
C -0.074 0.06 7.4 420
(X
0
/V
d
)e
-K1t
((k
mu1
X
0
/V
dm
)/(K1-K2))(e
-K2t
-e
-K1t
)
D -0.082 0.074 8.2 840
k
u
X
0
e
-K1t
((k
mu1
k
m1
X
0
)/(K1-K2))(e
-K2t
-e
-K1t
)
E -0.10 0.135 9.4 940
k
f
X
0
e
-K1t
((k
mu1
k
m1
X
0
)/(K1-K2))(e
-K1t
-e
-K2t
)
F -0.135 0.5 10 5676
(k
u
/K1) X
0
(1-e
-K1t
) ((k
mu1
X
0
)/(K1-K2))(e
-K2t
-e
-K1t
)
G -0.37 0.6 12 13500
(k
f
/K1) X
0
(1-e
-K1t
) ((k
mf1
k
m1
X
0
)/(K1-K2))((1-e
-K2t
)/K2-(1-e
-K1t
)/K1)
H -0.50 0.74 13.5 15700
((k
m1
X
0
)/(K1-K2))(e
-K2t
-e
-K1t
) ((k
mf1
k
m1
X
0
)/(K1-K2))((1-e
-K1t
)/K1-(1-e
-K2t
)/K2)
I -0.6 0.82 15.5 18000
((k
m1
X
0
)/(K1-K2))(e
-K1t
-e
-K2t
) ((k
mu1
k
m1
X
0
)/(K1-K2))((1-e
-K2t
)/K2-(1-e
-K1t
)/K1)
J -0.74 0.94 18 76700
((k
mu1
X
0
)/(K1-K2))(e
-K2t
-e
-K1t
) ((k
mf2
k
m1
X
0
)/(K1-K2))((1-e
-K2t
)/K2-(1-e
-K1t
)/K1)
14.8.3 FOSINOPRIL SOLUTIONS
X
Xm2
Xm1 Xmu1
Xmu2
ku=0
kmu1
kmu2
km1
km2
K1= km1
K2= kmu1+km2
K3= kmu2
10
1
10
2
Concentration
0
5
10
15
20
25
R
e
s
p
o
n
s
e
R vs Ln(c)
0 2 4 6 8 10 12 14
Time (hr)
15
16
17
18
19
20
21
22
23
R
e
s
p
o
n
s
e
R vs T
1 2 3 4 5 6
10
10
Fosinoprilat
Time (hr)
0
2
3
C
o
n
c
e
n
t
r
a
t
i
o
n

n
g
/
m
L
0 5 10 15 20 25
10
10

Time (hr)
E
x
c
r
e
t
i
o
n

R
a
t
e

(
m
g
/
h
r
)
-1
0
Fosinoprilat in Urine
1) X, the mass of parent drug, Fosinopril, in the body B - X
0
e
-K1t
) Xu, the mass of parent drug, Fosinopril, in urine. A - none(no drug goes there)
3) dXu/dt, the rate of excretion of parent drug, Fosinopril, in urine A = none(no drug goes there)
4) Xf, the mass of parent drug, Fosinopril, in feces. A = none(no drug goes there)
5) Xm1, the mass of metabolite, Fosinoprilat, in the body H = (k
m1
X
0
)/(K1-K2)(e
-K2t
-e
-K1t
)
6) Xm1u, the mass of metabolite, Fosinoprilat, in urine. I =
7) dXm1u/dt, the rate of excretion of metabolite, Fosinoprilat, in urine. D =
8) Xm1f, the mass of metabolite, Fosinoprilat, in feces. A = none(no drug goes there)
9) Cp, the plasma concentration of parent drug, Fosinopril C =
10) Cpm1, the plasma concentration of metabolite, Fosinoprilat. A =
Find the value of:
11) dR/dT I = -0.6 mm Hg/hr
12) dR/d(ln(Cpm1)) D = 8.2 mm Hg
13) d(ln(Cpm1))/dT C = -0.074 hr
-1
14) k
u
, the renal excretion rate constant of parent drug, Fosinopril, in plasma. A = none(no drug goes there)
15) k
m1
, the metabolism rate constant of parent drug, Fosinopril, in plasma. F = 0.5 hr
-1

16) k
mu1
, the renal excretion rate constant for metabolite, Fosinoprilat, in plasma. B = 0.037 hr
-1

17) k
m2
, the metabolism rate constant for the metabolite of Fosinoprilat in plasma. B = 0.037 hr
-1

18) K
1
, the elimination rate constant of parent drug in plasma , the summation of all processes which remove Fosinopril. F = 0.5 hr
-1

19) K
2
, the elimination rate constant of metabolite in plasma , the summation of all processes which remove Fosinoprilat. D = 0.074 hr
-1

For fosinoprilat IV, find the value of :
20) AUC
(fosinoprilat)
F = 5676 ng/mL
21) AUMC
(fosinoprilat)
J = 76700 mg/mL*hr
2
22) MRT(fosinoprilat) H = 13.5 hr
k
mu1
k
m1
X
0
( )
K1 K2 ( )
--------------------------------
1 e
K2t
K2
---------------------
1 e
K1t
K1
---------------------

' ;

k
mu1
k
m1
X
0
( )
K1 K2 ( )
-------------------------------- e
K2t
e
K1t
{ }
X
0
V
d
------
,
_
e
K1t
k
m1
X
0
K1 K2 ( )V
d
-------------------------------- e
K2t
e
K1t
{ }
-1
) D = 0.074 hr
-1

24) for Fosinoprilat (hr) E = 9.4 hr
25) Cp
0(fosinoprilat)
for iv dose (ng/mL) C = 420 ng/mL
26) Vd for Fosinoprilat (L) J = 18 L
27) Cp of Fosinoprilat at eight hours after the IV dose B = 232 ng/mL
For fosinoprilat given as IV fosinopril, dXm1/dt, find the value of :
28) AUC
(fosinoprilat)
(mg) F = 10 mg
29) AUMC
(fosinoprilat)
A = 155 mg*hr
30) MRT
(fosinoprilat)
I = 15.5 hr
31) K2 for fosinoprilat (hr
-1
) D = 0.074 hr
-1

32) T
?
for Fosinoprilat (hr) E = 9.4 hr
33) K1 for fosinopril (hr
-1
) F = 0.5 hr
-1

T
1 2
14.9 Omeprazole
14.9.1 OMEPRAZOLE DATA
Omeprazole (mw: 345.42) is a gastric proton-pump inhibitor which decreases gastric acid secretion. It is effective in
the treatment of ulcers and esophageal reflux. In normal patients, 20% of the omeprazole is excreted into the feces and
80% of the omeprazole dose is excreted as an inactive metabolite into the urine. In the study by Anderson, et. al., eight
patients were given 20 mg, IV bolus doses of omeprazole. The patients had a mean body weight of 70 kg. Blood and
urine were collected at various intervals throughout the study and the following data was obtained:
TABLE 14-2 Pharmacological Response
% Acid Secretion
Inhibition Time (min)
% Acid Secretion
Inhibition
Concentration
(ng/mL)
100 120 74 1
100 240 62 .6
75 330 56 .5
63 360 47 .35
56 375 27 .15
50 390
25 450
10 570
8 600
0 720
TABLE 14-3 Plasma profile of parent and urine profile of metabolite
Parent Compound
Intercept = 4 mg/hr
AUMC
met
= 96 mg*hr
Time (hr) Cp (ng/mL)
Urine Collection
Interval (hr)
Metabolite
collected (mg)
0.5 336 0 - 1 1.19
1 205 1 - 2 2.07
2 75 2 - 3 2.10
3 28 3 - 5 3.44
4 10 5 - 7 2.38
7 - 9 1.62
9 - 11 1.08
11 - 13 0.72
13 - 15 0.48
16 - 20 0.44
14.9.2 OMEPRAZOLE QUESTIONS
Using LaPlace transforms, from Omeprazole, given by IV bolus, find the equation
for:
1. 1) X, the mass of Omeprazole in the body
2. ) Xu, the mass of Omeprazole in urine.
3. ) dXu/dt, the rate of excretion of Omeprazole in urine.
4. ) Xf, the mass of Omeprazole in feces.
5. ) Xm, the mass of metabolite of Omeprazole in the body
6. ) Xmu, the mass of metabolite of Omeprazole in urine.
7. ) dXmu/dt, the rate of excretion of metabolite of Omeprazole in urine.
8. ) Xmf, the mass of metabolite of Omeprazole in feces.
9. ) Cp, the plasma concentration of parent drug, Omeprazole
10. ) Cpm, the plasma concentration of metabolite of Omeprazole.
Find the value of:
11. ) dR/dT = slope of the Pharmacological response vs. time profile (% / hr)
12. ) dR/d(lnC) = slope of the Pharmacological response vs concentration profile (%)
13. ) d(lnC)/dt = slope of the concentration vs time profile (hr
-1
)
14. ) k
r
= urinary excretion rate constant Omeprazole (hr
-1
)
15. ) k
f
= fecal excretion rate constant Omeprazole (hr
-1
)
16. ) k
m
= rate of metabolism of Omeprazole in the body (hr
-1
)
17. ) K1 = elimination rate constant of Omeprazole in the body; the summation of all of the ways that it
is removed from the body. (hr-1 )
18. ) T
1/2
of Omeprazole in the body (hr)
19. ) X
0
= Mass of Omeprazole in the body at time 0 (mg)
20. ) X
inf
= Mass of Omeprazole in the body at time infinite time (mg)
21. ) Xu
inf
= Mass of unchanged Omeprazole in the urine at infinite time (mg)
22. ) Xf
inf
= Mass of unchanged Omeprazole in the feces at infinite time (mg)
23. ) V = Volume of distribution of Omeprazole (L)
24. ) Cp
0
= Concentration of Omeprazole in the body at time 0. (mic/L)
25. ) AUC
iv
= Area under the plasma concentration of Omeprazole vs time curve of the IV
dose (mic/L*hr)
26. ) First trapazoid of the AUCiv (mic/L*hr)
27. ) Last trapazoid of the AUC
iv
(mic/L*hr)
28. ) AUMC
iv
= Area under the first moment of the plasma concentration of Omeprazole vs
time curve of IV dose (mic/L*hr2 )
29. ) MRT
iv
= Mean Residence time of Omeprazole given as the IV dose (hr)
30. ) X
m
= Mass of metabolite in the body at time = 0 (mg)
31. ) Xm
inf
= Mass of the metabolite in the body at infinite time. (mg)
32. ) V
m
= Volume of distribution of the metabolite in the body (L)
33. ) Cp
m
= Concentration of metabolite in the body at time = 0 (mic/L)
34. ) AUC
met
= Area Under the Curve of the metabolite excretion rate vs time profile (mg)
35. ) Xmu
0
= Mass of metabolite in urine at time = 0 (mg)
36. ) Xmu
inf
= Mass of metabolite in urine at time = infinity (mg)
37. ) Xmf
0
= Mass of metabolite in feces at time = 0 (mg)
38. ) Xmf
inf
= Mass of metabolite in feces at time = infinity (mg)
39. ) K
mu
= Rate constant of excretion of metabolite into urine (hr-1 )
40. ) K
mf
= Rate constant of excretion of metabolite into feces (hr-1 )
TABLE 14-4 Omeprazole Answer Pool
Minus Small Med Large Equations More Equations
A -0.8 0 1 100 None
B -1 0.1 2 147
C -2 0.2 4 210
D -4 0.3 8 223
E -8 0.4 10 372
F -10 0.5 16 444
G -16 0.6 20 556
H -20 0.7 25 643
I -25 0.8 36 756
k
m
X
0
K
1
K
2
( )V
dm
---------------------------------- e
K
2
t
e
K
1
t
( )
X
0
e
K
1
t
k
m
X
0
K
1
K
2
( )V
dm
---------------------------------- e
K
1
t
e
K
2
t
( )
X
0
Vd
-------
,
_
e
K
1
t k
mu
X
0
K
1
K
2
( )V
dm
---------------------------------- e
K
2
t
e
K
1
t
( )
k
u
X
0
e
K
1
t
k
mu
k
m
X
0
K
1
K
2
( )
----------------------- e
K
2
t
e
K
1
t
( )
k
f
X
0
e
K
1
t
k
mu
k
m
X
0
K
1
K
2
( )
----------------------- e
K
1
t
e
K
2
t
( )
k
u
K
1
------
,
_
X
0
1 e
K
1
t
( )
k
mu
X
0
K
1
K
2
( )
----------------------- e
K
2
t
e
K
1
t
( )
k
f
K
1
------
,
_
X
0
1 e
K
1
t
( )
k
mf
k
m
X
0
K
1
K
2
( )
-----------------------
1 e
K
2
t
K
2
---------------------
,

_
1 e
K
1
t
K
1
---------------------
,

_
k
m
X
0
K
1
K
2
( )
----------------------- e
K
2
t
e
K
1
t
( )
k
mf
k
m
X
0
K
1
K
2
( )
-----------------------
1 e
K
1
t
K
1
---------------------
,

_
1 e
K
2
t
K
2
---------------------
,

_
k
m
X
0
K
1
K
2
( )
----------------------- e
K
1
t
e
K
2
t
( )
k
mu
k
m
X
0
K
1
K
2
( )
-----------------------
1 e
K
2
t
K
2
---------------------
,

_
1 e
K
1
t
K
1
---------------------
,

_

J -36 0.9 44 893
A Missing Information. Can not answer question with information available
Minus Small Med Large Equations More Equations
k
mu
X
0
K
1
K
2
( )
----------------------- e
K
2
t
e
K
1
t
( )
k
mu
k
m
X
0
K
1
K
2
( )
-----------------------
1 e
K
1
t
K
1
---------------------
,

_
1 e
K
2
t
K
2
---------------------
,

_

14.9.3 OMEPRAZOLE SOLUTIONS
kf
km
kmu
X Xf
Xm Xmu

10
-1
10
0
20
30
40
50
60
70
80

340 360 380 400 420 440 460
20
30
40
50
60
70
80
320
R
e
s
p
o
n
s
e
R
e
s
p
o
n
s
e
Concentration
Time (min)
0 2 4 6 10 12
10
10
10

8
0 5 10 15 20
10
10
10
C
o
n
c
e
n
t
r
a
t
i
o
n
C
o
n
c
e
n
t
r
a
t
i
o
n
Time (hr)
Time (hr)
1. (B)
2. (A) See model.
3. (A) See model.
4. (G)
5. (H)
6. (I)
7. (D)
8. (A) See model.
9. (C)
10.(A)
11.(I) Estimate from graph. Between 20-80% of maximal
response ONLY!
12.(H) Points taken from sample graph.
13.(B)
14.(A) See model.
15.(C) Also, is 20% of , or 20% of 1hr
-1
=
0.2hr
-1
16.(I) if you have .or
. Also, is 80% of , or 80% of 1hr
-1
=
0.8hr
-1
17.(A)
18.(H)
19.(G) Read introduction.
20.(A) See model.
21.(A)
X X
0
e
K
1
t
=
X
u
0 =
dX
u
dt
--------- 0 =
Xf
k
f
K
1
------
,
_
X
0
1 e
K
1
t
( ) =
X
m
k
m
X
0
K
1
K
2
( )
----------------------- e
K
2
t
e
K
1
t
( ) =
X
mu
k
mu
k
m
X
0
K
1
K
2
( )
-----------------------
1 e
K
2
t
K
2
---------------------
,

_
1 e
K
1
t
K
1
---------------------
,

_
=
dX
mu
dt
-------------
k
mu
k
m
X
0
K
1
K
2
( )
----------------------- e
K
2
t
e
K
1
t
( ) =
X
mf
0 =
C
p
X
0
Vd
-------
,
_
e
K
1
t
=
C
pm
k
m
X
0
K
1
K
2
( )V
dm
---------------------------------- e
K
2
t
e
K
1
t
( ) =
dR
dt
-------
0.4%
minute
------------------
25%
hr
--------------
dR
d C
p
ln
---------------
74%-57%
1.0
ng
ml
------ 0.5
ng
ml
------ ln ln
----------------------------------------------
17%
0.693
------------- 25% = =
d C
p
ln
dt
---------------
dR
dt
-------
d C
p
ln
dR
---------------
25%
hr
--------------
1
25%
----------- 1 hr
1
= = =
k
r
0 =
k
f
X
f
K
1
X
0
--------------
4mg 1hr
1
20mg
----------------------------- 0.2hr
1
= = = k
f
K
1
k
m
K
1
k
f
1hr
1
0.2hr
1
0.8hr
1
= = = k
f
k
m
X
mu
K
1
X
0
----------------
16mg 1hr
1
20mg
-------------------------------- 0.8hr
1
= = = k
m
K
1
K
1
d C
p
ln
dt
------------------ 1hr
1
= =
t
1 2
0.693
K
1
------------- 0.693 0.7hr = =
X
0
20mg =
X
inf
0 =
X
u inf ( )
0 =
22.(C) 20% of parent excreted in feces (read introdction).
23.(I)
24.(G) From graph.
25.(G) or
or
26.(D)
27.(E)
28.(G)
29.(A) or
30.(A) See model.
31.(A) See model.
32.(A) Can not determine from information given. Need information.
33.(A) See model.
34.(F) . AUC is equal to all drug which goes
through compartment, which is 80% of the 20 mg dose, or 16 mg (read intro-
duction).
35.(A) See model.
36.(F) 80% of the 20 mg dose is found as metabolite in
urine (Read introduction).
37.(A) See model.
38.(A) See model.
X
f inf ( )
20
100
--------- 20mg 4mg = =
V
d
Dose
C
p0
-------------
20mg
556
ng
mL
--------
-----------------
20 000g ,
556
g
L
------
------------------------- 36L =
C
p0
556
ng
mL
-------- 556
g
L
------
AUC
IV
C
p n ( )
C
p n 1 + ( )
+
2
---------------------------------------
,
_
t
C
p last ( )
K
1
------------------ +
= AUC
IV
C
p0
K
1
--------- =
AUC
IV
556 336 +
2
------------------------ 0.5
,
_
336 205 +
2
------------------------ 0.5
,
_
205 75 +
2
--------------------- 1
,
_
75 28 +
2
------------------ 1
,
_
28 10 +
2
------------------ 1
,
_
10
1
------
+ + + +
+ 578.75 556
g hr
L
-----------------
=
=
AUC
IV
556
ng
mL
--------
1hr
----------------- 556
hr
L
------------- = =
556 336 +
2
------------------------ 0.5
,
_
223
g hr
L
----------------- =
10
1
------
g hr
L
-----------------
AUMC
IV
t
n
C
p n ( )
t
n 1 +
C
p n 1 + ( )
+
2
--------------------------------------------------------
,
_
t
C
p last ( )
K
1
( )
2
------------------
t
last
C
p last ( )
K
1
---------------------------- + +
=
AUMC
IV
0 556 ( ) 0.5 336 ( ) +
2
--------------------------------------------- 0.5
,
_
0.5 336 ( ) 1 205 ( ) +
2
--------------------------------------------- 0.5
,
_
1 205 ( ) 2 75 ( ) +
2
------------------------------------- 1
,
_
2 75 ( ) 3 28 ( ) +
2
---------------------------------- 1
,
_
3 28 ( ) 4 10 ( ) +
2
---------------------------------- 1
,
_
10
1
2
------
4 10 ( )
1
--------------
+ + +
+ + + 541.75 556
g hr
2
L
-------------------
=
=
MRT
IV
AUMC
AUC
------------------
556
g hr
2
L
-------------------
556
g hr
L
-----------------
----------------------------- 1hr = MRT
IV
1
K
1
------
1
1hr
1
-------------- 1hr = = =
Xm
0
0 =
X
m inf ( )
0 =
V
dm
= C
pm
C
pm0
0 =
AUC
met
X
mu
80
100
--------- 20mg 16mg = = =
X
mu0
0 =
X
mu inf ( )
80
100
--------- 20mg 16mg = =
X
mf0
0 =
X
mf inf ( )
0 =
39.(C) = is from urine data graph because
which is .
40.(A) See model.
k
mu
K
2
0.2hr
1
= = k
small
k
l e arg
1hr
1
K
1
K
mf
0 =
14.10 EXP3312, an Experimental Drug
Wong N, Wong P. (J Pharm Pharmacol 1996; 48: 492-497) investigated the phar-
macological and pharmacokinetic response of EXP3312
14.10.1 EXP3312 DATA
EXP3312 is a non-peptide angiotension II AT1-receptor antagonist which has
potential as an oral hypertensive drug. EXP3312 a pro-drug is metabolized to an
active metabolite M1. Experiments with rats show M1 is the active drug. As with
all angiotension II antagonists EXP3312 blocks the renin-angiotension system.
EXP3312 is a synthesized analog of Losartin, but EXP3312 has greater oral
hypotensive potency and has promise in future treatment of human renal hyperten-
sion. EXP3312 is still an experimental drug without all pharmacological responses
having been explored. However, we may assume the drug is completely metabo-
lized to the active metabolite (M1). Thereafter, the active metabolite (M1) is
excreted unchanged in the urine.
The following pharmalogical data was obtained using pithed (spinal tap) rats with
an average weight of 350 g. The concentration of drug in each rat is based on aver-
age weights of the rats. The measured responses of decrease in mean arterial pres-
sure (MAP decrease) are shown below.The researchers supplied graphical data of
mean arterial pressure in conscious renal hypertensive rats. M1 metabolite was
measured and the results are also shown in the table below.
TABLE 14-5
Response (mm Hg) M1 administration (mg/kg) Response (mm Hg) Time (hr)
(MAP) decrease I.V. bolus (MAP) decrease
25 0.01 60 0
36.5 0.03 57.4 1
48.5 0.1 54.7 2
59 0.3 49.3 4
44.5 6
The parent compound EXP3312 and metabolite M1 levels were measured in the
plasma over time. The data obtained from the active M1 metabolite and the inac-
tive partent drug EXP3312 are shown below. The standard dose for each rat was
0.3mg/kg.
Use the following data was obtained when an intravenous infusion of a different
dose was given to an average rat over 45 minutes.
TABLE 14-6
EXP3312 M1
time (hr) Cp (mic/mL) Cp (mic/mL)
0.15 0.32
0.3 0.59
0.5 0.4
1 0.26 1.34
2 0.11 1.61
3 0.045
4 1.26
6 0.81
10 0.3
12 0.18
I = 3.81 mic/mL
TABLE 14-7
time (hr) Plasma concentration
(mic/mL)
0.25 0.139
0.5 0.26
0.75 0.35
1 0.29
2 0.12
3 0.05
14.10.2 EXP3312 & M1 QUESTIONS:
Using the information given find the pharmacokinetic parameters (CHECK
YOUR UNITS!!!!!!):
1. dR/dt of M1 active metabolite (mmHg/hr)
2. dR/d(lnCp) active metabolite (mmHg)
3. d(lnCp)/dt of M1active metabolite (hr
-1
)
4. The slope of Cp vs: t of EXP3312 on semi-log paper (hr
-1
)
5. The slope of terminal portion of dXmu/dt vs: t (mid) on semi-log paper (hr
-1
)
6. The slope of stripped portion of Cpm vs: t or (Concentration of M1 vs: t) on semi-log paper
(hr
-1
)
7. The equation for X in the body.
8. The equation for Xm or M1 in the body.
9. K1 (elimination rate constant of EXP3312) (hr-1)
10. ku (urinary excretion rate constant of EXP3312) (hr-1)
11. km (metabolism rate constant of M1 (hr-1)
12. kmu (urinary excretion rate constant of M1 (hr-1)
13. Cp
0
(Initial IV bolus concentration of EXP3312) (mic/ml)
14. Vd of EXP3312 (L)
15. Vdm of M1 (L)
16. AUC (Cp vs: t for EXP3312 by IV bolus) (mic/mL*hr))
17. AUMC (t*Cp vs: t for EXP3312 by IV bolus) (mic/mL* hr
2
))
18. MRT for EXP3312 (hr)
19. AUC (dXu/dt vs: t (mid) for EXP3312 by IV bolus) (mg)
20. AUC (dXmu vs: t (mid) for M1) (mg)
21. X
0
(EXP3312 in the body at time zero) (mg)
22. Xmu
0
(M1in the urine at time zero) (mg)
23. Xm
0
(M1 in the body at time zero) (mg)
24. X at 2hr (EXP3312 in the body at 2 hr.) (mg)
25. Xm at 2hr (M1 in the body at 2 hr.) (mg)
26. X
inf
(EXP3312 in the body at infinite time) (mg)
27. Xu
inf
(EXP3312 in the urine at infinite time) (mg)
28. Xm
inf
(M1in the body at infinite time) (mg)
29. T
1/2
(EXP3312) (hr)
30. Clearance of EXP3312 (L/hr)
EXP3312 Infusion Questions:
31. K (elimination rate constant of EXP3312) (hr-1)
32. T1/2 (EXP3312) (hr)
33. Volume of distribution (L/kg)
34. Clearance (L/hr/kg)
35. How long will it take to reach 95% steady state? (hr)
36. Q (infusion rate) (mg/hr)
37. Find the plasma concentration if the infusion in Table 14-7 on page 58 was discontinued at 5
hours instead of 45 minutes. (mic/mL)
38. Find the time need for the concentration to drop to 0.23 mic/mL after the infusion in question 37
is discontinued (hours).
39. Determine the new infusion rate necessary to maintain a plasma concentration of Cpss 1.0 mic/
mL of the average rat. (mg/hr)
40. Find a loading dose for the average rat which would give the Cpss of 1.0 mic/mL immediately
(mg)
This exam is given early at the request of those students who had conflict with the time agreed upon. They signed a
document stating that they would not share their experience with anyone under pain of prosecution for adademic mis-
conduct which will result minimally in an F for the course. You also must sign this document.
I ___________________________________________ did not comunicate in anyway anything at all regarding this
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prosecution for adademic misconduct.
Signed__________________________________________________________Date__________________
TABLE 14-8 Answer Pool
Minus
ones
Small
ones
Big
ones
Bigger
ones
Equations Equations
A -0.121 0 0.55 1.05
None
B -0.26 0.019 0.62 1.15
C -0.391 0.039 0.72 1.32
D -0.567 0.063 0.80 1.69
E -0.621 0.105 0.83 2.63
F -0.866 0.146 0.866 3.5
G -1.112 0.169 0.94 4.17
H -1.981 0.26 0.95 4.83
I -2.63 0.42 0.96 7.2
J -3.71 0.48 0.99 10.1
k
m
X
0
K
1
K
2
( )Vd
m
---------------------------------- e
K
2
t
e
K
1
t
( )
X
0
e
K
1
t
k
m
X
0
K
1
K
2
( )Vd
m
---------------------------------- e
K
1
t
e
K
2
t
( )
X
0
Vd
-------
,
_
e
K
1
t k
mu
X
0
K
1
K
2
( )V
dm
---------------------------------- e
K
2
t
e
K
1
t
( )
k
u
X
0
e
K
1
t
k
mu
k
m
X
0
K
1
K
2
( )
----------------------- e
K
2
t
e
K
1
t
( )
k
f
X
0
e
K
1
t
k
mu
k
m
X
0
K
1
K
2
( )
----------------------- e
K
1
t
e
K
2
t
( )
k
u
K
1
------
,
_
X
0
1 e
K
1
t
( )
k
mu
X
0
K
1
K
2
( )
----------------------- e
K
2
t
e
K
1
t
( )
k
f
K
1
------
,
_
X
0
1 e
K
1
t
( )
k
mf
k
m
X
0
K
1
K
2
( )
-----------------------
1 e
K
2
t
K
2
---------------------
,

_
1 e
K
1
t
K
1
---------------------
,

_
k
m
X
0
K
1
K
2
( )
----------------------- e
K
2
t
e
K
1
t
( )
k
mf
k
m
X
0
K
1
K
2
( )
-----------------------
1 e
K
1
t
K
1
---------------------
,

_
1 e
K
2
t
K
2
---------------------
,

_
k
m
X
0
K
1
K
2
( )
----------------------- e
K
1
t
e
K
2
t
( )
k
mu
k
m
X
0
K
1
K
2
( )
-----------------------
1 e
K
2
t
K
2
---------------------
,

_
1 e
K
1
t
K
1
---------------------
,

_
k
mu
X
0
K
1
K
2
( )
----------------------- e
K
2
t
e
K
1
t
( )
k
mu
k
m
X
0
K
1
K
2
( )
-----------------------
1 e
K
1
t
K
1
---------------------
,

_
1 e
K
2
t
K
2
---------------------
,

_

14.11 Graph Paper
0 1
0
5

CHAPTER 15 Practice Exams: Exam 2
Practice Exams: Exam 2
15.1 Nifedipine: Exam 2
Nifedipine (Procardia @) is a calcium channel blocker which specifically inhibits potential-dependent channels not
receptor-operated channels, preventing calcium influx of cardiac and vascular smooth muscle (coronary, cerebral).
Calcium channel blockers reduce myocardial contractility and A-V node conduction by reducing the slow inward cal-
cium current. They are indicated in angina, cardiac dysrhythmias, and hypertension among others. Nifedipine
appears to be metabolized entirely into an inactive metabolite, an acid and subsequently further metabolized to a lac-
tone. Both the acid and the lactone are excreted into the urine and the feces.
Hepatic blood flow in normals is 1.6 L/min
Renal blood flow in normals is 1.2 L/min
Echizen and Eichelbaum (Clin Pkin 1986; 11:425-49) and Kleinbloesem et al (Clin Pcol Therap 1986; 40: 21-8)
reviewed the pharmacokinetics of Nifedipine. While the drug is not routinely given by IV bolus and does not strictly
conform to a one compartment model, let's treat the data as if those problems can be ignored. The following data is
offered for evaluation:
TABLE 1-1. Nifedipine IV Bolus Profile
Time (hr) Cp (mcg/L) Cm1 (mcg/L) Xm1f (mg) Xm1u (mg) Xm2f (mg) Xm2u (mg)
0.5 24.7
1 44.4
2 139 71.8 .14 .59
4 65.6 96.5 .44 1.83 .028 .11
6 31.1 100 .77 3.25 .073 .29
8 14.6 94.7 1.1 4.65 .135 .54
12 76.5 1.69 7.10 .291 1.15
24 34 2.77 11.63 .75 2.95
7 days 3.6 15.1 1.3 5.0
TABLE 1-2 Nifedipine Oral information
Brand Generic
Route IV Oral Capsule Oral Capsule
Dose (mg)
25
10 10
AUC (ug/L*hr) 785 236 204
AUMC (ug/L*hr2 ) 2093 866 816
Practice Exams: Exam 2 : Nifedipine: Exam 2
15.1.1 NIFEDIPINE QUESTIONS:
Find:
1) MRT iv (hr)
2) Ke (elimination rate constant) for Nife-
dipine (hr-1 )
3) T 1/2 for Nifedipine
4) Cp0 for iv dose (ug/L)
5) Vd for Nifedipine (L)
7) Cp of Nifedipine at one hour after the
IV dose
8) AUC from 0 to one hour for the IV dose
9) Total Body Clearance of Nifedipine (L/
hr)
10) Renal Clearance of Nifedipine (L/hr)
11) Hepatic Clearance of Nifedipine (L/hr)
12) Renal Extraction Ratio
13) Hepatic Extraction Ratio
14) Absolute bioavailability for the brand
name capsule
15) MRT (oral brand name capsule) (hr)
16) MAT (oral brand name capsule) (hr)
17) Ka, the apparent absorbtion rate con-
stant, for the brand name capsule (hr-1 )
18) Peak time for the brand name capsule
(hr)
19) Cpmax , the maximum concentration
of the brand name oral capsule give as a
single dose (ug/L)
20) Absolute bioavailability for the generic
capsule
21) MRT (oral generic capsule) (hr)
22) MAT (oral generic capsule) (hr)
stant, for the generic capsule (hr-1 )
24) Peak time for the generic capsule (hr)
of the generic oral capsule give as a single
dose (ug/L)
26) Comparative bioavailability of the oral
capsules
Your patient is controlled by 20 mg TID
of the brand name oral capsule when he
is healthy.
27) What is his N for that dosing regimen?
28) Cpssmax for this patient at this dosing
regimen (ug/L)
29) Cpssavg for this patient at this dosing
regimen (ug/L)
30) Cpssmin for this patient at this dosing
regimen (ug/L)
You want to maintain his plasma con-
centrations between 110% of Cpssmax
and 90% of Cpssmin . How would you
change the dosage regimen to if your
patient suffered from:
31) stenosis of the kidney (Fr = 0.67).
32) renal failure (Fi = 0.67).
33) stenosis of the liver (Fr = 0.67)
34) cirrhosis of the liver (Fi = 0.67)
TABLE 1-3 Nifedipine Answer Pool
Small Medium Large
Dosing changes:
a) 0.00 a) 1.85 a) 59 a) 10 mg once daily
b) 0.05 b) 2.67 b) 85 b) 10 mg BID
c) 0.33 c) 3.67 c) 92.5 c) 10 mg TID
d) 0.375 d) 4.0 d) 101 d) 10 mg QID
e) 0.65 e) 4.32 e) 124 e) 20 mg once daily
f) 0.75 f) 9.3 f) 147 f) 20 mg BID
g) 0.85 g) 18.5 g) 185 g) 20 mg TID (no change necessary)
h) 1.0 h) 32 h) 202 h) 20 mg QID
i) 1.33 i) 38 i) 248 i) 30 mg once daily
j) 1.57 j) 49 j) 294 j) 30 mg BID
15.1.2 NIFEDIPINE SOLUTIONS
1.
2.
3.
4.
5.
6. skip (error in numbering)
7.
8.
9.
10.
11.
12.
13.
14. Absolute bioavailability for brand
name capsule = 0.75
15. Oral brand name capsule
18. Oral brand name peak time
19. Oral brand name
20. Absolute bioavailability for
generic = 0.65
21. Oral generic capsule
24. Oral generic capsule peak time
26. Comparative bioavailability of the
oral capsules B/A:
AUC = 0.86 (ok)
Peak time = 1.18 (ok)
Cpmax = 0.78 (not ok!)
27.
28.
29.
30.
31. No change
32. No change
33. No change
34. No change
MRT
iv
2.67hr =
k
e
0.375hr
1
=
T
1 2
1.85hr =
Cp
0
294ug L =
Vd 85L =
Cp
1
202ug L =
AUC
0 1
248ug L hr =
Cl
s
32L hr =
Cl
r
0 =
Cl
h
32L hr =
E
r
0 =
E
h
0.33 =
MRT 3.67hr =
MAT 1.0hr =
Ka 1.0hr
1
=
1.57hr
Cp
max
49ug L =
MRT 4hr =
MAT 1.33hr =
Ka 0.75hr
1
=
1.85hr
Cp
max
38ug L =
N 4.32 =
Cp
ss
max 185ug L =
Cp
ss
ave 59ug L =
Cp
ss
min
9.3ug L =
Practice Exams: Exam 2 : Valproate: Exam 2
15.2 Valproate: Exam 2
All questions are internally consistent. Information gained in any one can be used in all others. Note, however, there
is a change in patient status midway through.
Valproate is a carboxylic acid anticonvulsant. Its activity may be related, at least in part, to increase concentra-
tions of the neurotransmitter inhibitor gamma aminobutyric acid in the brain. It is used alone or in combination
with other anticonvulsants. in the prophylactic management of petit mal. It appears to be almost entirely cleared
by liver function with negligible amounts excreted into the urine unchanged. It comes as soft gelatin capsules of 250
mg and enteric coated tablets 250 and 500 mg. The therapeutic range for valproate appears to be between 20 and 100
mic/ml. The volume of distribution is 0.19 L/Kg and your patient is 70 kg.
TABLE 1-4
IV bolus Brand Generic
Dose (mg) 500 250 250
AUC (mg/L*hr) 594 273 253
AUMC(mg/L*hr
2
)
9428.6 4605.5 4184.6
T
peak
(hr) 2.95
Cp
max
14.35
Bioavailability (f) 1.0 .92
15.2.1 VALPROATE QUESTIONS
1) Calculate the MRT
iv
of Valproate (hr).
a) 11 b) 15.87 c) 16.54 d) 16.87 e) 17.08
2) Calculate the rate constant of elimination (hr
-1
) in normals ?
a) 0.091 b) 0.063 c) 0.060 d) 0.0593 e) 0.0585
3) Calculate the half life of Valproate (hr)?
a) 7.6 b) 11 c) 11.5 d) 11.7 e) 11.8
4) Calculate the hepatic clearance of valproate (L/hr).
a) 0.0084 b) 0.063 c) 0.84 d) 1.25 d) 2.5
5) Calculate the hepatic extraction ratio of valproate.
a) 0.0063 b) 0.0084 c) 0.063 d) 0.084 e) 0.84
6) What is the maximum N for multiple dosing of Valproate?
a) 0.78 b) 1.65 c) 2.12 d) 2.32 e) 2.5
7) What is the maximum acceptable dosing interval for normal patients (hr)?
a) 8 b) 12 c) 18 d) 24 e) 25.5
8) What is the N if we are going to dose TID?
a) 0.63 b) 0.727 c) 0.842 d) 1.25 e) 1.42
9) If you dosed this patient 500 mg BID with the brand name product, what would be your maximum concentration at
steady state (mg/L)?
a) 87.3 b) 70.9 c) 65.2 d) 52.8 e) 45.8
10) What would be your minimum concentration at steady state (mg/L)?
a) 52.8 b) 32.7 c) 30.1 d) 27.1 e) 22.9
11) What would be your average concentration at steady state (mg/L)?
a) 63.8 b) 49.8 c) 47.7 d) 45.8 e) 34.4
12) What loading dose would you give to get to Cpss right away (mg)?
a) 250 b) 500 c) 750 d) 1000 e) 1500
13) If you changed the dosage regimen to 250 mg QID, what would happen to the Cpssmax, Cpssave, Cpssmin?
a) Cpssmax - up, Cpssave - up, Cpssmin - up
b) Cpssmax - down, Cpssave - down, Cpssmin - down
c) Cpssmax - same, Cpssave - same, Cpssmin - same
d) Cpssmax - up, Cpssave - same, Cpssmin - down
e) Cpssmax - down, Cpssave - same, Cpssmin - up
14) Calculate f, the absolute bioavailability of the generic product.
a) 0.67 b) 0.75 c) 0.85 d) 0.93e) 1.0
15) Calculate the comparative bioavailability of the generic product.
a) 0.67 b) 0.75 c) 0.85 d) 0.93e) 1.0
16) Calculate the MRT
oral
of the generic product.
a) 11 b) 15.87 c) 16.54 d) 16.87 e) 17.08
17) Calculate the MAT of the generic product.
a) 0.67 b) 0.75 c) 0.85 d) 0.93e) 1.0
18) Calculate the Ka of the generic product.
a) 1.5 b) 1.33 c) 1.18 d) 1.08 e) 1.0
19) Calculate the peak time of the generic product.
a) 2.21 b) 2.45 c) 2.59 d) 2.76 e) 2.95
20) Calculate the Cp
max
of the generic product.
a) 8.1 b) 9.3 c) 10.7 d) 12.6 e) 14.4
21) Is the generic product bioequivalent?
a) Yes
b) No, because the comparative bioavailability is outside the federal guidelines.
c) No, because the ratio of the peak times is outside the federal guidlines.
d) No, because the ratio of the Cp
max
s is outside the federal guidlines.
e) No, because the generic fails more than one of the required comparisons.
In patients who are also currently on phenobarbital their intrinsic clearance of valproate increases by 50% as the phe-
nobarbital induces the enzymes which metabolize valproate. Further questions refer to this condition.
22) Calculate his new clearance.
a) 0.0084 b) 0.063 c) 0.84 d) 1.25 d) 2.5
23) Calculate his new K.
a) 0.095 b) 0.084 c) 0.063 d) 0.059 e) 0.042
24) Calculate his new maximum acceptable dosing interval (hr).
a) 8 b) 12 c) 17 d) 18 e) 24
25) What dosage regimen would you recommend to try to maintain his plasma concentrations within 110% of the max-
imum and 90% of the minimum concentrations attained when he was normal?
a) 750 mg BID b) 500 mg TID c) 750 mg TID d) 250 mg QID e) 500 mg QID
15.2.2 VALPROATE SOLUTIONS
Practice Exams: Exam 2 : Methyl phenidate
15.3 Methyl phenidate
Methyl phenidate (MP) (Ritalin@) is an effective stimulant in the treatment of narcolepsy in adults and attention deficit
syndrome in children. It is entirely metabolized to the inactive metabolite, Ritalinic Acid (RA), by the liver which is
subsequently excreted unchanged into the urine. The following information was obtained from a 70 Kg male.
Q
H
= 24 mL/min/Kg
Q
R
= 19 mL/min/Kg
TABLE 1-6 Ritalin Answer Pool
TABLE 1-5 Ritalin Data
IV
Brand
Name Generic
Dose (mg) 10 20 20
AUC (ug/ml*hr) 0.20 0.04 0.035
AUMC (ug/ml*hr
2
0.32 0.14 0.1225
Itty- Bitty Tiny Puny Small Medium Large Words
a 0 0.016 0.1 1.1 10 100 yes
b 0.00016 0.0251 0.125 1.6 20 125 no, Ratio of Tps
c 0.0005 0.035 0.25 1.75 30 225 no, Ratio of Cmaxs
d 0.00074 0.042 0.35 1.9 40 375 no, Ratio of AUCs
e 0.00084 0.05 0.42 2.6 50 435 no, Ratio of AUMCs
f 0.0016 0.067 0.53 3.5 60 550 no, more than one criterion
g 0.005 0.075 0.625 4.2 70 675 20 mg TID
h 0.0074 0.0875 0.727 5.0 80 750 20 mg BID
i 0.0084 0.091 0.875 7.27 90 875 20 mg QD
j 0.0090 0.096 0.91 8.75 96 995 20 mg QID
15.3.1 METHYL PHENIDATE QUESTIONS:
1) MRT iv (hr)
2) Ke (elimination rate constant) for
Ritalin (hr
-1
)
3) T
1/2
for Ritalin (hr)
4) Cp
0
for iv dose (ug/mL)
5) Vd for Ritalin (L)
6) Cp of Ritalin at one hour after the IV
dose
8) Total Body Clearance of Ritalin (L/hr)
9) Renal Clearance of Ritalin (L/hr)
10) Hepatic Clearance of Ritalin (L/hr)
11) Intrinsic Hepatic Clearance of Ritalin
(L/hr)
name tablet
15) MRT (oral brand name tablet) (hr)
16) MAT (oral brand name tablet) (hr)
stant, for the brand name tablet (hr
-1
)
18) Peak time for the brand name tablet
(hr)
19) Cp
max
, the maximum concentration of
the brand name oral tablet give as a single
dose (ug/mL)
tablet
21) MRT (oral generic tablet) (hr)
22) MAT (oral generic tablet) (hr)
stant, for the generic tablet (hr
-1
)
24) Peak time for the generic tablet (hr)
25) Cp
max
, the maximum concentration of
the generic oral tablet give as a single dose
(ug/mL)
tablets
27) Are the tablets bioequivalent?
Your patient is controlled by 20 mg TID of
the brand name oral tablet when he is
healthy. For This patient and this dosage
regimen, what is his:
28) N ?
29) Cp
ss
max
(ug/mL)
30) Cp
ss
avg
(ug/mL)
31) Cp
ss
min
(ug/mL)
You want to maintain his plasma concen-
trations between 110% of Cp
ss
max
and 90% of
Cp
ss
min
. How would you change the dosage
regimen to if your patient suffered from:
(in no case was there a change in Vd)
32) stenosis of the kidney (Fr = 0.67)?
33) renal failure (Fi = 0.34)?
34) stenosis of the liver (Fr = 0.67)?
35) cirrhosis of the liver. (Fi = 0.67)?
36) treatment with phenobarbital (Fi =
1.33)?
15.3.2 METHYL PHENIDATE SOLUTIONS:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14. Brand name -
15. Brand name -
16. Brand name -
17. Brand name -
18. Brand name -
19. Brand name -
20. Generic -
21. Generic -
22. Generic -
23. Generic -
24. Generic -
25. Generic -
26. Comparative bioavailability =
0.875
27. Yes, the tablets are bioequivalent -
all parameters are within federal guide-
lines.
28.
29.
30.
31.
32. 20 mg TID
33. 20 mg TID
34. 20 mg BID
35. 20 mg TID
36. 20 mg QID
MRT
iv
1.6hr =
k 0.625hr
1
=
T
1 2
1.1hr =
Cp
0
0.125ug mL =
Vd 80L =
Cp
1
0.067ug mL =
AUC
0 1
0.096ug mL hr =
Cl
s
50L hr =
Cl
r
0 =
Cl
h
50L hr =
Cl
int
100L hr =
E
r
0 =
E
h
0.53 =
f 0.1 =
MRT 3.5hr =
MAT 1.9hr =
Ka 0.526hr
1
=
T
peak
1.74hr =
Cp
max
0.0084ug mL =
f 0.0875 =
MRT 3.5hr =
MAT 1.9hr =
Ka 0.53hr
1
=
T
peak
1.75hr =
Cp
max
0.0074ug mL =
N 7.27 =
Cp
ss
max
0.0251ug mL =
Cp
ss
avg 0.005ug mL =
Cp
ss
min 0.00016ug mL =
Practice Exams: Exam 2 : Verapamil
15.4 Verapamil
Verapamil is a calcium channel blocker with vasodilatory and antiarrhythmic effects. It is about 95% metabolized by
the liver with the metabolites showing up in the urine and feces.
Hepatic blood flow in normals is 1.6 L/min
Renal blood flow in normals is 1.2 L/min
TABLE 1-7 Verapamil Data
TABLE 1-8 Verapamil Answer Pool
Brand Generic
Route IV Oral Tablet Oral Tablet
Dose (mg) 15 80 80
AUC (ng/mL*hr) 300 480 400
AUMC (ng/mL*hr2 ) 1600 2690 2280
Tiny Small Medium Large Dosing regimens Bioavailability answers
a 0 1.06 26 116 40 mg qd Yes
b 0.063 2.15 46 267 40 mf bid No, tp ratio is not within limits
c 0.188 2.50 47.5 369 40 mg tid No, Cpmax ratio is not within limits
d 0.250 2.70 50 533 40 mg qid No, AUC ratio is not within limits
e 0.270 3.69 56 637 80 mg qd No, f ratio is not within limits
f 0.300 5.33 61.5 830 80 mg bid No, ka ratio is not within limits
g 0.370 5.60 76.5 905 80 mg tid No, ke ratio is not within limits
h 0.693 5.70 83 970 80 mg qid No, MRT ratio is not within limits
i 0.85 6.37 90.5 1160 160 mg qd No, Cl ratio is not within limits
j 0.905 8.30 97 2670 160 mg bid No, more than one of the required ratios are no within limits
15.4.1 VERAPAMIL QUESTIONS
1) MRT iv (hr)
2) Ke (elimination rate constant) for Vera-
pamil (hr-1 )
3) T 1/2 for Verapamil
4) Cp0 for iv dose (ug/L)
5) Vd for Verapamil (L)
7) Cp of Verapamil at one hour after the IV
dose
9) Total Body Clearance of Verapamil (L/
hr)
10) Renal Clearance of Verapamil (L/hr)
11) Hepatic Clearance of Verapamil (L/hr)
name tablet
stant, for the brand name tablet (hr-1 )
18) Peak time for the brand name tablet
(hr)
of the brand name oral tablet give as a sin-
gle dose (ug/L)
tablet
stant, for the generic tablet (hr-1 )
of the generic oral tablet give as a single
dose (ug/L)
tablets
Your patient is controlled by 80 mg TID
of the brand name oral tablet when he is
healthy.
28) What is his N for that dosing regimen?
29) Cpssmax for this patient at this dosing
regimen (ug/L)
30) Cpssavg for this patient at this dosing
regimen (ug/L)
31) Cpssmin for this patient at this dosing
regimen (ug/L)
You want to maintain his plasma con-
centrations between 110% of Cpssmax
and 90% of Cpssmin . How would you
change the dosage regimen to if your
patient suffered from:
32) stenosis of the kidney (Fr = 0.67). (No
change in volume of distribution.)
33) renal failure (Fi = 0.34).(Volume of
distribution is reduced in this disease to
50% of normal)
34) stenosis of the liver (Fr = 0.67) (No
change in volume of distribution)
35) cirrhosis of the liver (Volume of Dis-
tribution and the bioavailability are both
doubled while the half life is quadrupled )
15.4.2 VERAPAMIL SOLUTIONS
1.
2.
3.
4.
5.
6. skip - error in numbering
7.
8.
9.
10.
11.
12.
13. Correction - should
be added to answer pool
14. Brand name tablet - absolute bio-
availability = 0.30
15. Brand name tablet -
18. Brand name tablet - peak time -
20. Generic - Absolute bioavailability
-
21. Generic -
22. Generic -
23. Generic -
24. Generic -
25. Generic -
26. Comparative bioavailability - 0.85
27. The tablets are not bioequivalent -
peak time ratio is not within limits.
28.
29.
30. (change in
answer pool)
31.
32. No change in dosing regimen - 80
mg TID
MRT
iv
5.33hr =
k
e
0.188hr
1
=
T
1 2
3.69hr =
Cp
0
56ug L =
Vd 267L =
Cp
1
47ug L =
AUC
0 1
50ug L hr =
Cl 50L hr =
Cl
r
2.50L hr =
Cl
h
47.5L hr =
E
r
0.063 =
E
h
0.49 =
MRT 5.60hr =
MAT 0.270hr =
Ka 3.69hr
1
=
0.85hr
Cp
max
76.5ug L =
f 0.25 =
MRT 5.7hr =
MAT 0.37hr =
Ka 2.70hr
1
=
T
peak
1.06hr =
Cp
max
61.5ug L =
N 2.15 =
Cp
ss
max 116ug L =
Cp
ss
avg 60ug L =
Cp
ss
min
26ug L =
33. 40 mg TID
34. No change in dosing regimen - 80
mg TID
35. 40 mg BID
Practice Exams: Exam 2 : Hydromorphone hydrochloride
15.5 Hydromorphone hydrochloride
Hydromorphone hydrochloride is an analog of morphine which has about seven times the analgesic effect of morphine
when given by IV. It is about 90% metabolized. The following data was obtained by Valner et al J.Clin Pcol 21(1981)
152-6:
TABLE 1-9 Hydromorphone hydrochloride Data
IV
Oral tablet
Brand
Oral tablet
Generic
Dose (mg) 2 4 4
AUC (ng/mL*hr) 83 87 65
AUMC (ng/mL*hr
2
)
291 348 292
15.5.1 HYDROMORPHONE HYDROCHLORIDE QUESTIONS
For the IV product, find:
1. MRTiv. (291/83=3.5)
2. K. (1/3.5=0.285
3. T1/2 (0.693/.285= 2.4 hr)
4. Cp0 (AUC*K = 83*0.285= 23.7ng/mL
5. Ku (0.1*0.285=0.029)
6. Km (0.9*0.285=0.256)
7. Cls (f*D/AUC=1*2000/83=24L/hr)
8. Vd (Cls/K=Vd= 24/0.285=84L
9. Clh (0.9*Cls = 21.6 L/hr
10. Clr (0.1*Cls = 2.4 L/hr
11. Eh (21.6 / (24 mL/min * 60 min * 70 Kg /
1000mL/L) = 0.2
12. Er ( 2.4 / ( 10 ml/min * 60 min * 70 Kg /
1000mL/L) = 0.06
For the Brand name oral tablet, find:
13. MRT (348/87=4.0)
14. MAT(4 - 3.5 = 0.5)
15. Ka (1/0.5 = 2.0)
16. Tp (ln(ka/K)/(ka-K)=1.95/1.715=1.14hr
17. Absolute bioavailability, f ((87/4)/(83/
2)=0.52
18. Cpmax (18 ng/mL)
For the Generic oral tablet, find:
19. MRT ( 292/65=4.5 hr)
20. MAT (4.5 - 3.5 = 1 hr)
21. ka (1/MAT = 1/1=1 hr-1)
22. Tp (ln(1/0.285)/(1-0.285)=1.26/.715=1.76
hr
23. Absolute bioavailability, f ((65/4)/(83/
2)=0.39
24. Cpmax (11 ng/mL)
Would you consider the oral tablets to
be bioequivalent? Why or why not?
25. No R(Tp) = 1.54 fail
26. R(Cp) = 0.61 fail
27. R(Bio)= 0.75 fail
You would like to dose your healthy
patient using the brand name tablet so
that his plasma concentration is in the
therapeutic range of 35 to 5 ng/mL.
Find:
28. Nmax (ln(35/5)/ln(2) = 2.8
29. Taumax (2.8*2.4=6.74 hr
30. Maximum acceptable tau = 6
31. N (6/2.4 =2.5)
32. What dosage regimen would you recom-
mend? (4mg q6h)
33. Cpssmax? (30 ng/mL)
34. Cpssavg? (14 ng/mL)
35. Cpssmin? ( 5 ng/mL)
He gets renal stenosis (Fr = 0.5) with no
change in Vd. Find:
36. FClr0.94
37. Clr*2.3
38. FClh1
39. Clh*21.6
40. FCls.99
41. Cls*23.9
42. K*0.284
43. t1/2*2.44
44. Nmax 2.8
45. Taumax6.83
46. Maximum acceptable tau 6
47. N 2.46
mend? 4mg q6h
49. Cpssmax? 30
50. Cpssavg? 15
51. Cpssmin? 5.5
His stenosis of the kidney clears and he
now goes into renal dysfunction
(Fi=0.5), find:
52. FClr.52
53. Clr*1.23
54. FClh2
55. Clh*21.6
56. FCls.95
57. Cls*22.8
58. K*0.271
59. t1/2*2.55
60. Nmax 2.8
61. Taumax 7.13
62. Maximum acceptable tau6
63. N 2.35
mend? 4mg q6h
65. Cpssmax? 31
66. Cpssavg? 15
67. Cpssmin? 6.1
His renal dysfunction clears and now he
suffers from stenosis of the liver
(Fr=0.5), Find:
68. FClr1
69. Clr*2.4
70. FClh.833
71. Clh*18
72. FCls.85
73. Cls*20.4
74. K*.243
75. t1/2*2.85
76. Nmax 2.8
77. Taumax8
78. Maximum acceptable tau 8
79. N 6
mend? 4 mg q6h
81. Cpssmax? 32
82. Cpssavg? 17
83. Cpssmin? 7.5
His stenosis of the liver clears and he
now suffers from liver dysfunction
(Fi=0.05), Find:
84. FClr1
85. Clr*2.4
86. FClh.56
87. Clh*12
88. FCls.6
89. Cls*14.4
90. K*.171
91. t1/2*4.04
92. Nmax 2.8
93. Taumax11.3
94. Maximum acceptable tau8
95. N 1.48
mend?4 mg q8h
97. Cpssmax? 33
98. Cpssavg? 18
99. Cpssmin?8.4
15.6 Fosinopril Sodium
Fosinopril Sodium (MW 585) is a phosphinic prodrug of the angiotensin converting enzyme (ACE) inhibitor fosinopri-
lat (MW 563). After oral administration, fosinopril is slowly and incompletely absorbed, and is converted to the active
fosinoprolat by esterases in the gastrointestinal mucosa and the liver. Unlike other ACE inhibitors, elimination of fosi-
noprilat is divided equally between renal and hepatic pathways. With the IV dose fosinoprilat was given and mea-
sured. With the oral dose fosinopril was given but fosinoprilat was measured. The following information was obtained
from a 70 Kg male. This information was constructed from Kostis et al Fosinopril: Pharmacokinetics and pharmaco-
dynamics in congestive heart failure Clin Pcol Ther 58(6) 660-5 (1995); Hui et al Pharmacokinetics of fosinopril in
patients with various degrees of renal function Clin Pcol Ther 49(4) 457 -66 (1991)
Q
H
= 24 mL/min/Kg Blood
Q
R
= 19 mL/min/Kg Blood
TABLE 1-10 Fosinopril Data
IV Brand Name
Tablet
Generic
Tablet
Dose (mg) 7.5 10 10
AUC (ng/ml*hr) 5700 1500 1400
AUMC (ng/ml*hr
2
)
78000 25000 23100
TABLE 1-11 Fosinopril Answer Pool:
a 0 0.015 0.19 1.3 10 100 yes
b 0.00016 0.0251 0.21 1.6 13.7 142 no, Ratio of Tps
c 0.0005 0.035 0.25 1.75 16.6 192 no, Ratio of Cmaxs
d 0.00074 0.042 0.36 1.9 18 253 no, Ratio of AUCs
e 0.00084 0.05 0.42 2.8 50 387 no, Ratio of AUMCs
f 0.0016 0.067 0.53 3.5 67 402 no, more than one criterion
g 0.005 0.073 0.65 4.0 73 416 10 mg qid
h 0.0064 0.0875 0.72 5.6 84 750 10 mg tid
i 0.0084 0.091 0.84 7.0 93 875 10 mg bid
j 0.0090 0.096 0.93 9.5 96 995 10 mg qd
15.6.1 FOSINOPRIL QUESTIONS
1) MRT for fosinoprilat (hr)
-1
)
3) T
?
for Fosinoprilat (hr)
4) Cp
0
for iv dose (ng/mL)
5) Vd for Fosinoprilat (L)
6) Cp of Fosinoprilat at one hour after the IV dose
8) Total Body Clearance of Fosinoprilat (L/hr)
9) Renal Clearance of Fosinoprilat (L/hr)
10) Hepatic Clearance of Fosinoprilat (L/hr)
11) Intrinsic Hepatic Clearance of Fosinoprilat (L/hr)
14) Absolute bioavailability for the brand name tablet
17) Ka, the apparent absorption rate constant, for the brand name tablet (hr
-1
)
18) Peak time for the brand name tablet (hr)
19) Cp
max
, the maximum concentration of the brand name oral tablet give as a single dose (ng/mL)
20) Absolute bioavailability for the generic tablet
23) Ka, the apparent absorption rate constant, for the generic tablet (hr
-1
)
25) Cp
max
, the maximum concentration of the generic oral tablet give as a single dose (ng/mL)
26) Comparative bioavailability of the oral tablets
Your patient is controlled by 10 mg TID of the brand name oral tablet when he is
healthy. For This patient and this dosage regimen, what is his:
28) N ?
29) Cp
ss
max
(ng/mL)
30) Cp
ss
avg
(ng/mL)
31) Cp
ss
min
(ng/mL)
You want to maintain his plasma concentrations between 120% of Cp
ss
max
and 80% of
Cp
ss
min
. How would you change the dosage regimen to if your patient suffered from:
(in no case was there a change in Vd)
32) stenosis of the kidney (Fr = 0.67)?
33) renal failure (Fi = 0.34)?
34) stenosis of the liver (Fr = 0.67)?
35) cirrhosis of the liver. (Fi = 0.67)?
36) treatment with phenobarbital (Fi = 1.5)?
Practice Exams: Exam 2 : Fosinopril Sodium
15.6.2 FOSINOPRIL SODIUM SOLUTIONS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11. Intrinsic Hepatic Clearance is
12.
13.
14. Oral brand name tablet absolute
bioavailability is 0.21
15. Oral brand name tablet
18. Oral brand name tablet peak time
20. Oral generic tablet absolute bio-
availability is 0.19
21. Oral generic tablet
22. Oral generic tablet
23. Generic tablet
24. Generic tablet peak time
25. Generic tablet
26. Comparative bioavailability of the
oral tablets = 0.93
27. Yes! the tablets are bioequivalent
The AUCs, peak times, and s are
all within 20% range.
28.
29.
30.
31.
32. 10 mg TID
33. 10 mg BID
34. 10 mg TID
35. 10 mg TID
36. 10 mg QID

MRT 13.7hr =
k 0.073hr
1
=
T
1 2
9.5hr =
Cp
0
416ng mL =
Vd 18L =
Cp
1
387ng mL =
AUC
0 1
402ng mL =
Cl
s
1.3L hr =
Cl
r
0.65L hr =
Cl
h
0.65L hr =
0.65L hr
E
r
0.015 =
E
h
0.0064 =
MRT 16.6hr =
MAT 2.8hr =
Ka 0.36hr
1
=
5.6hr
Cp
max
0.073ng mL =
MRT 16.6hr =
MAT 2.8hr =
Ka 0.36hr
1
=
5.6hr
Cp
max
0.067ng mL =
Cp
max
N 0.84 =
Cp
ss
max
253ng mL =
Cp
ss
avg
192ng mL =
Cp
ss
min
142ng mL =
15.7 Remoxipride
Remoxipride (MW 296 - Unionized Base pKa 9.4) is a new antipsychotic of the benzamide type (See figure 1). The
pharmacokinetics were studied by Movin-Osswald and Hammarlind-Udenaes (Brit. J Clin Pcol 1991 32(3) 355ff).
Their results are summarized in table 1. The HCl salt of the drug was given (MW 332.5) to these patients in this study
but the drug concentration was reported as the free base in the plasma. In this study, 25% of the Remoxipride was
excreted unchanged, 75% was metabolized. The hepatic and renal blood flow in these patients was 1.5 and 1.2 L/min
respectively. REMEMBER TO PAY ATTENTION TO UNITS.
FIGURE 4-5. Remoxipride
TABLE 1-12 Remoxipride Data
IV bolus Oral Solution Tablet A Tablet B
Dose (mg) 50 100 100
AUMC (umole/
L*hr2 )
145 158.7 319.6 282.6
AUC (umole/L*hr) 20.9 19.8 37.6 31.4

Tp (hr) 3.6
Cpmax (mg/L) .8
f .75
15.7.1 REMOXIPRIDE QUESTIONS
1) Find the MRT of the IV product (hr).
2) Find the elimination rate constant of remoxipride (hr-1 ).
3) Find the Cp0 of the IV product (mg/L)
4) Find the volume of distribution of the IV product. (L)
5) Find the half life of remoxipride (hr).
6) Find the clearance of remoxipride (L/hr).
7) Find the renal clearance (L/hr).
8) Find the hepatic clearance
9) Find the renal extraction ratio.
10) Find the hepatic extraction ratio.
11) Find the MRT of remoxipride given as the oral solution (hr).
12) Find the MAT of remoxipride given as oral solution (hr).
13) Find the absorption rate constant of remoxipride given as an oral solution (hr-1 ).
14) Find the bioavailability of the oral solution (f).
15) Find the peak time of the oral solution (hr).
16) Find the MRT of remoxipride given as Tablet A, the brand name product.
17) Find the MAT of remoxipride given as Tablet A.
18) Find the apparent absorption rate constant (ka) of remoxipride given as Tablet A.
19) Find the peak time of Tablet A.
20) Find the single dose Cpmax for tablet A (mg/L)
21) Find the mean dissolution time (MDT) of Tablet A, the brand name product (hr).
22) Is Tablet B, the generic product is bioequivalent to Tablet A. Why or why not?
23) Find N for BID dosing.
24) Find Cpss max for two caps bid for the brand name product.
25) Find Cpss avg for two caps bid for the brand name product.
26) Find Cpss min for two caps bid for the brand name product.
27) Which change in physiological status would result in the most significant change in
the TBC of remoxipride?
a) Changes which effect the flow of blood to the liver.
b) Changes which effect the flow of blood to the kidney.
c) Changes which effect the function of the liver.
d) Changes which effect the function of the kidney.
Your patient is experiencing that change. That physiological function was up 75% above
normal (F = 1.75).
28) Find his new renal clearance
29) Find his new hepatic clearance.
30) Find his new total body clearance.
31) Assuming now change in volume of distribution, find his new half life.
32 Assuming no change in dosage regimen, find his new N.
33 What dosing regimen would you recommend to return his plasma concentrations back
to normal (within 110% of max and 90% of min)?
15.7.2 REMOXIPRIDE SOLUTIONS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11. Oral solution
12. Oral solution
13. Oral solution
14. Oral solution bioavailability
15. Oral solution peak time
16. Tablet A
17. Tablet A
18. Tablet A
19. Tablet A peak time
20. Tablet A single dose
21. Tablet A
22. Tablet B is not bioequivalent to Tablet A because peak time and are out of
federal guidelines.
23. For dosing BID,
MRT 6.93hr =
k
e
0.144hr
1
=
Cp
0
0.88mg L =
Vd 50L =
T
1 2
4.8hr =
Cl 7.28L hr =
Cl
r
1.8L hr =
Cl
h
5.46L hr =
E
r
0.025 =
E
h
0.06 =
MRT 8hr =
MAT 1.07hr =
Ka 0.935hr
1
=
f 0.95 =
2.4hr
MRT 8.5hr =
MAT 1.57hr =
Ka 0.637hr
1
=
3.0hr
Cp
max
1.03mg L =
MDT 0.5hr =
Cp
max
N 2.5 =
24.
25.
26.
27. The change in physiological status that would result in the most significant change
in TBC of remoxipride is (C) - changes
which effect the function of the liver.
28. New renal clearance = no change
29. New
30. New
31. New
32. New
33. The dosing regimen to recommend = 200 mg TID
Cp
ss
max
3.88mg L =
Cp
ss
avg 1.85mg L =
Cp
ss
min 0.685mg L =
Cl
h
9.0L hr =
Cl
s
10.8L hr =
T
1 2
3.2hr =
N 3.75 =
15.8 Naproxen
Naprosyn
@
(naproxen) is a nonsteroidal anti-inflammatory drug (NSAID) with
analgesic properties. It is well absorbed (f = 0.95) and highly protein bound (98%)
with a volume of distribution of about 10 L and a half-life of 13 hours in normal
adults. It is almost entirely cleared by hepatic function (CL
r
= 1%) with about one-
third being metabolized to the 6-o-desmethylnaproxen (which is further metabo-
lized by conjugation) and two-thirds being conjugated directly. Both the 6-o-des-
methyl metabolites as well as the conjugates are inactive.
Normal dosing is 500 mg Naproxen BID. You stock 200 and 500 mg tablets in
your HMO.
For the following conditions, new parameters are given in parentheses.
Concomitant treatment with Probenecid, a uricosuric which increases the urinary
excretion of uric acid, while not interfering with the protein binding, effectively
blocks the hepatic conjugation process reducing the hepatic function (Cl
inth
) to
one-third of normal.
In chronic renal failure (F
ir
= 0.1) the protein binding is reduced (94%) because of
uremia. This results in a marginal increase in half-life (14 hr.)
In rheumatoid arthritis, hypoalbuminaemia results in a reduction in protein binding
(97%) and increase in the volume of distribution (13 L).
Elderly patients exhibit a decrease in binding (96%), but no change in half-life or
volume of distribution.
For each of the conditions, (with Probenecid, chronic renal failure, arthritic, and
elderly), please recommend a dosage regimen which would give approximately the
same plasma concentrations of free naproxen obtained in the normal case (+ 10%.)
Constants:
Extraction ratios are calculated for normals and considered to be constant through-
out.
Q
r
0.0191
L
min kg
-------------------- renal blood perfusion 70kg 60
min
hr
--------- 80
L
hr
-----blood =
Q
H
0.0238
L
min kg
-------------------- hepatic blood perfusion 70kg 60
min
hr
--------- 100
L
hr
-----blood =
15.8.1 NAPROXEN QUESTIONS
TABLE 1-1. Question Numbers For Exam
Patient Condition Normal Probenecid
treatment
Chronic
Renal Failure
Rheumatoid
arthritis
Elderly
Dose(mg) 1 27 51 75 99
f 2 28 52 76 100
f
u
3 29 53 77 101
V
d
(L) 4 30 54 78 102
k (hr
-1
)
5 31 55 79 103
T
1/2
(hr) 6 32 56 80 104
AUC (mg/L*hr) 7 33 57 81 105
%
8 34 58 82 106
%
9 35 59 83 107
(L/hr)
10 36 60 84 108
(L/hr)
11 37 61 85 109
(L/hr)
12 38 62 86 110
13
14
(L/hr)
15 39 63 87 111
(L/hr)
16 40 64 88 112
17 41 65 89 113
18 42 66 90 114
19 43 67 91 115
20 44 68 92 116
F
CL
21 45 69 93 117
(hr)
22 46 70 94 118
N 23 47 71 95 119

24 48 72 96 120
Cl
h
Cl
r
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
FR
h
FI
h
FR
r
FI
r
Cp
ss
max
free
g
mL
--------
,
_
25 49 73 97 121
26 50 74 98 122
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
Answer Pool
S M L XL XXL XXXL
A 0.000067 0.0182 0.100 1.0 10.0 100
B 0.0005 0.0200 0.133 1.1 11.3 200
C 0.0050 0.0300 0.177 1.4 12.0 303
D 0.0080 0.0400 0.182 1.5 13.0 356
E 0.0089 0.0495 0.267 1.6 13.3 500
F 0.0092 0.0533 0.315 1.7 14.0 595
G 0.0095 0.0600 0.333 1.8 26.5 891
H 0.0097 0.0610 0.341 1.9 31.7 1044
I 0.0098 0.0675 0.528 2.0 38.1 2000
J 0.0099 0.0700 0.533 2.1 45.0 3000
A 0.0790 0.577 2.2 50.0
B 0.0798 0.615 2.9 53.0
C 0.0857 0.675 3.0 62.0
D 0.0923 0.700 5.3 80.0
E 0.0950 0.790 6.2 86.0
F 0.0970 0.798 8.0 92.0
G 0.0990 0.857 8.5 97.0
I 0.0999 0.923 9.0 99.0
J 0.09997 0.95 9.9 99.97
15.8.2 NAPROXEN SOLUTIONS
TABLE 1-1. Question Numbers For Exam
Patient Condition Normal Probenecid
treatment
Chronic
Renal Failure
Rheumatoid
arthritis
Elderly
Dose(mg) 1. 500 mg 27. 200 51. 500 75. 500 99. 200
f 2. 0.95 28. 0.95 52. 0.95 76. 0.95 100. 0.95
f
u
3. 0.02 29. 0.02 53. 0.06 77. 0.03 101. 0.04
V
d
(L) 4. 10 30. 10 54. 31.67 78. 13 102. 10
k (hr
-1
)
5. 0.0533 31. 0.0182 55. 0.0495 79. 0.061 103. 0.533
T
1/2
(hr) 6. 13 32. 38.1 56. 14 80. 11.3 104. 13
AUC (mg/L*hr) 7. 891 33. 1044 57. 303 81. 595 105. 356
%
8. 99 34. 97 58. 99.97 82. 99 106. 99
%
9. 1 35. 3 59. 0.03 83. 1 107. 1
(L/hr)
10. 0.533 36. 0.182 60. 1.57 84. 0.798 108. 0.533
(L/hr)
11. 0.528 37. 0.177 61. 1.57 85. 0.790 109. 0.528
(L/hr)
12. 0.005 38. 0.005 62. 0.005 86. 0.008 110. 0.005
13. 0.005
14. 0.000067
(L/hr)
15. 26.5 39. 8.84 63. 26.5 87. 26.5 111. 13.26
(L/hr)
16. 0.267 40. 0.267 64. 0.00889 88. 0.267 112. 0.133
17. 1 41. 1 65. 1 89. 1 113. 1
18. 1 42. 0.333 66. 3 90. 1.5 114. 1
19. 1 43. 1 67. 1 91. 1 115. 1
20. 1 44. 1 68. 0.1 92. 1.5 116. 1
F
CL
21. 1 45. 0.341 69. 2.94 93. 1.5 117. 1
(hr)
22. 12 46. 12 70. 12 94. 12 118. 8
Cl
h
Cl
r
Cl
tot
Cl
h
Cl
r
E
h
E
r
Cl
h
int
Cl
r
int
FR
h
FI
h
FR
r
FI
r

N 23. 0.923 47. 0.315 71. 0.857 95. 1.06 119. 0.615

24. 2.01 48. 1.94 72. 2.01 96. 2.1 120. 2.2
25. 1.5 49. 1.74 73. 1.5 97. 1.5 121. 1.78
26. 1.06 50. 1.55 74. 1.1 98. 1.01 122. 1.42
Cp
ss
max
free
g
mL
--------
,
_
Cp
ss
avg
free
g
mL
--------
,
_
Cp
ss
min
free
g
mL
--------
,
_
15.8.3
1. Dose = 500 mg (given)
2. Bioavailability (f) = 0.95 (given)
3. Unbound Fraction = 0.02 (given)
4. (given)
5.
6. (given)
7.
8.
9. (given)
10.
11.
12.
13.
14.
15.
16.
17. (given)
18. (given)
V
d
10L =
k
0.693
t
1 2
------------- 0.0533hr
1
= =
t
1 2
13hr =
AUC
f Dose
k V
d
------------------- 891L = =
%Cl
h
100 %Cl
r
99 = =
%Cl
r
1 =
Cl
tot
k V
d
0.533L hr = =
Cl
h
Cl
tot
%Cl
h
0.528L hr = =
Cl
r
Cl
tot
%Cl
r
0.005L hr = =
E
h
Cl
h
Q
h
-------- 0.00528 = =
E
r
Cl
r
Q
r
-------- 0.000067 = =
Cl
h
int
Q Cl
h
Q Cl
h
------------------
f
u
------------------- 26.5L hr = =
Cl
r
int
Q Cl
r
Q Cl
r
------------------
f
u
------------------ 0.267L hr = =
FR
h
1 =
FI
h
1 =
19. (given)
20. (given)
21. (given)
22. (given)
23.
24.
25.
26.
27. Dose = mg
28. Bioavailability (f) = 0.95 (no change)
29. Unbound Fraction = 0.02 (no change - given)
30. (given)
31.
32. (given)
33.
34.
35. (given)
36.
37.
FR
r
1 =
FI
r
1 =
F
Cl
1 =
12hr =
N

t
1 2
--------- 0.923 = =
Cp
ss
max
free
f
u
S f D
V
--------------------------
1
1
1
2
---
,
_
N
-------------------- 2.0
g
mL
-------- = =
Cp
ss
avg
free
f
u
S f D
V K
--------------------------
f
u
S f D
V 0.693 N
------------------------------ = 1.5
g
mL
-------- = =
Cp
ss
min
free
f
u
S f D
V
--------------------------
1
2
---
,
_
N
1
1
2
---
,
_
N
-------------------- 1.1
g
mL
-------- = =
V
d
10L =
k
0.693
t
1 2
------------- 0.0533hr
1
= =
t
1 2
13hr =
AUC
f Dose
k V
d
------------------- 891L = =
%Cl
h
100 %Cl
r
99 = =
%Cl
r
1 =
Cl
tot
k V
d
0.533L hr = =
Cl
h
Cl
tot
%Cl
h
0.528L hr = =
38.
39.
40.
41. (given)
42. (given)
43. (given)
44. (given)
45. (given)
46. (given)
47.
48.
49.
50.
51. Dose = mg
54. (given)
Cl
r
Cl
tot
%Cl
r
0.005L hr = =
Cl
h
int
Q Cl
h
Q Cl
h
------------------
f
u
------------------- 26.5L hr = =
Cl
r
int
Q Cl
r
Q Cl
r
------------------
f
u
------------------ 0.267L hr = =
FR
h
1 =
FI
h
1 =
FR
r
1 =
FI
r
1 =
F
Cl
1 =
12hr =
N

t
1 2
--------- 0.923 = =
Cp
ss
max
free
f
u
S f D
V
--------------------------
1
1
1
2
---
,
_
N
-------------------- 2.0
g
mL
-------- = =
Cp
ss
avg
free
f
u
S f D
V K
--------------------------
f
u
S f D
V 0.693 N
------------------------------ = 1.5
g
mL
-------- = =
Cp
ss
min
free
f
u
S f D
V
--------------------------
1
2
---
,
_
N
1
1
2
---
,
_
N
-------------------- 1.1
g
mL
-------- = =
V
d
10L =
55.
56. (given)
57.
58.
59. (given)
60.
61.
62.
63.
64.
65. (given)
66. (given)
67. (given)
68. (given)
69. (given)
70. (given)
71.
72.
k
0.693
t
1 2
------------- 0.0533hr
1
= =
t
1 2
13hr =
AUC
f Dose
k V
d
------------------- 891L = =
%Cl
h
100 %Cl
r
99 = =
%Cl
r
1 =
Cl
tot
k V
d
0.533L hr = =
Cl
h
Cl
tot
%Cl
h
0.528L hr = =
Cl
r
Cl
tot
%Cl
r
0.005L hr = =
Cl
h
int
Q Cl
h
Q Cl
h
------------------
f
u
------------------- 26.5L hr = =
Cl
r
int
Q Cl
r
Q Cl
r
------------------
f
u
------------------ 0.267L hr = =
FR
h
1 =
FI
h
1 =
FR
r
1 =
FI
r
1 =
F
Cl
1 =
12hr =
N

t
1 2
--------- 0.923 = =
Cp
ss
max
free
f
u
S f D
V
--------------------------
1
1
1
2
---
,
_
N
-------------------- 2.0
g
mL
-------- = =
73.
74.
75. Dose = mg
78. (given)
79.
80. (given)
81.
82.
83. (given)
84.
85.
86.
87.
88.
89. (given)
90. (given)
Cp
ss
avg
free
f
u
S f D
V K
--------------------------
f
u
S f D
V 0.693 N
------------------------------ = 1.5
g
mL
-------- = =
Cp
ss
min
free
f
u
S f D
V
--------------------------
1
2
---
,
_
N
1
1
2
---
,
_
N
-------------------- 1.1
g
mL
-------- = =
V
d
10L =
k
0.693
t
1 2
------------- 0.0533hr
1
= =
t
1 2
13hr =
AUC
f Dose
k V
d
------------------- 891L = =
%Cl
h
100 %Cl
r
99 = =
%Cl
r
1 =
Cl
tot
k V
d
0.533L hr = =
Cl
h
Cl
tot
%Cl
h
0.528L hr = =
Cl
r
Cl
tot
%Cl
r
0.005L hr = =
Cl
h
int
Q Cl
h
Q Cl
h
------------------
f
u
------------------- 26.5L hr = =
Cl
r
int
Q Cl
r
Q Cl
r
------------------
f
u
------------------ 0.267L hr = =
FR
h
1 =
FI
h
1 =
91. (given)
92. (given)
93. (given)
94. (given)
95.
96.
97.
98.
99. Dose = mg
102. (given)
103.
104. (given)
105.
106.
107. (given)
108.
109.
FR
r
1 =
FI
r
1 =
F
Cl
1 =
12hr =
N

t
1 2
--------- 0.923 = =
Cp
ss
max
free
f
u
S f D
V
--------------------------
1
1
1
2
---
,
_
N
-------------------- 2.0
g
mL
-------- = =
Cp
ss
avg
free
f
u
S f D
V K
--------------------------
f
u
S f D
V 0.693 N
------------------------------ = 1.5
g
mL
-------- = =
Cp
ss
min
free
f
u
S f D
V
--------------------------
1
2
---
,
_
N
1
1
2
---
,
_
N
-------------------- 1.1
g
mL
-------- = =
V
d
10L =
k
0.693
t
1 2
------------- 0.0533hr
1
= =
t
1 2
13hr =
AUC
f Dose
k V
d
------------------- 891L = =
%Cl
h
100 %Cl
r
99 = =
%Cl
r
1 =
Cl
tot
k V
d
0.533L hr = =
Cl
h
Cl
tot
%Cl
h
0.528L hr = =
110.
111.
112.
113. (given)
114. (given)
115. (given)
116. (given)
117. (given)
118. (given)
119.
120.
121.
122.
Cl
r
Cl
tot
%Cl
r
0.005L hr = =
Cl
h
int
Q Cl
h
Q Cl
h
------------------
f
u
------------------- 26.5L hr = =
Cl
r
int
Q Cl
r
Q Cl
r
------------------
f
u
------------------ 0.267L hr = =
FR
h
1 =
FI
h
1 =
FR
r
1 =
FI
r
1 =
F
Cl
1 =
12hr =
N

t
1 2
--------- 0.923 = =
Cp
ss
max
free
f
u
S f D
V
--------------------------
1
1
1
2
---
,
_
N
-------------------- 2.0
g
mL
-------- = =
Cp
ss
avg
free
f
u
S f D
V K
--------------------------
f
u
S f D
V 0.693 N
------------------------------ = 1.5
g
mL
-------- = =
Cp
ss
min
free
f
u
S f D
V
--------------------------
1
2
---
,
_
N
1
1
2
---
,
_
N
-------------------- 1.1
g
mL
-------- = =
CHAPTER 16 Exam 3
Author:
Reviewer:
Exam 3
16.1 Pharmacokinetics Final Exam
Summer 1996
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) with antidepressant properties. After oral
administration, the drug is almost completely absorbed from the gastrointestinal tract, however despite complete
absorption, oral bioavailibiliity in man is approximately 50% on account of first-pass hepatic metabolism. Steady-state
plasma concentrations are achieved within 5 to 10 days after initiation of therapy and are 30 to 50 % higher than those
predicted from single dose data. Fluvoxamine displays non-linear steady state pharmacokinetics over the therapeutic
dose range, with disproportionally higher plasma concentrations with higher dosages. Plasma protein binding of flu-
voxamine (77%) is low compared with that of other SSRIs.
V.L. is a 39 year old, 110# female suffering from severe depression. She was admitted to the hospital and pre-
scribed 100mg BID of Fluvoxamine but still her depression was uncontrolled at this dose. Her plasma concentration
on this regimen was 20ug/L. After her physician increased her dose to 300 mg BID her plasma concentration was 500
ug/L. V.L.s depression was controlled at this dose, however she was complaining of adverse effects. The therapeutic
range (total drug ug/L) of fluvoxamine is 20-500. Fluvoxamine is metabolized extensively (93%) by the liver to an
inactive metabolite.
1. What was her clearance on the 100 mg BID regimen (L/day)?
2. What was her clearance on the 300 mg BID regimen (L/day)?
3. What was her (mg/day)?
4. What was her (mg/L)?
5. The doctor would like to change her therapy in order to minimize side effects. What dose would you
recommend tolower her plasma concentration to 300 ug/L?
V.L. has major complications from a combined hepatitis B infection and cirrhosis of the liver. As a result her
protein binding is reduced to 66%, her changes to 0.03 mg/L and her changes to 100mg/day.
6. What would be her plasma concentration of total fluvoxamine if she maintained the regimen from
question 5 (mg/L)?
7. What is her free plasma concentation (mg/L)?
8. What total fluvoxamine plasma concentration would you recommend achieving to get her free fluvoxa-
mine plasma concentration back to that of the regimen in question 5 (mg/L)?
V
max
K
m
K
m
V
max
Exam 3
9. What daily dose of fluvoxamine (by I.V. bolus) would you recommend to get her average free fluvoxamine
plasma concentration approximately back to what it was when she was healthy (mg/day)?
Flurbiprofen is a nonsteroidal anti-inflammatory drug (NSAID) which is a potent inhibitor of prostaglandin
synthesis. It was introduced in the U.S. in 1986 for the treatment of osteoarthritis, rheumatoid arthritis, acute gouty
arthritis, and ankylosing spondylitis. Flurbiprofen is stereoselectively and extensively bound to plasma albumin.
Approximately 99% of the drug is metabolized by the liver, with trace amounts excreted in the urine as unchanged
drug. Flurbiprofen is 80% bioavailable. The recommended dosages for flurbiprofen are 50 mg q 4-6 hr as needed for
analgesia and 100-300 mg/day for the treatment of inflammatory conditions.
The following healthy and sick parameters are given for the patient V.L., 110# suffering from severe arthritis.
Her effective hepatic blood flow is 24 mL/min/kg and effective renal blood flow is 15.0 mL/min/kg. Her healthy half-
life is 6 hours. Dr. M. recommends 100 mg flurbiprofen BID.
Healthy Sick
0.15 L/kg 0.19L/kg
% Bound Drug 99.0% 97.0%
10. What is her total body clearance of flurbiprofen (L/hr)?
11. What is the intrinsic hepatic clearance (L/hr)?
12. What is the hepatic extraction ratio?
13. What is the of total flurbiprofen in mg/L?
14. What is the of total flurbiprofen in mg/L?
15. What is the of free flurbiprofen in mic/L?
16. What is the of free flurbiprofen in mic/L?
17. V.L. is now suffering from chronic renal insufficiency. Bound flurbiprofen has now decreased to 97%
due to significant uremia. What is her new hepatic clearance (L/hr)?
18. What is her new k?
19. What is the new N?
20. What would her dose be now, if you wanted to maintain approximately the same free plasma concentra-
tions as the previous therapy with the largest tau?
21. The renal insufficiency clears up and she comes down with mono. Her plasma albumin drops to 50% of
normal thus reducing the bound fraction to 96%. What is her new hepatic clearance using the healthy ?
22. What would her dose be now, if you wanted to maintain approximately the same plasma concentrations as
the previous therapy with the largest tau?
V
d
Cp
ss
max
Cp
ss
min
Cp
ss
max
Cp
ss
min
V
d
Exam 3
23. The mono clears up, but now there seems to be hepatic stenosis. Her plasma flow is reduced to 50% of
normal. What would her dose be now, if you wanted to maintain approximately the same concentrations
as the previous therapy with the largest tau?
Clentiazem is a chlorinated analog of diltiazem. It is currently undergoing clinical evaluation for the treatment
of angina pectoris and hypertension. The primary mechanism responsible for the antihypertensive effect of CLZ is a
decrease in peripheral vascular resistance due to the blockade of calcium channels. The following information was
obtained from a dose of 20 mg Clentiazem given I.V.

24. Can this data be adequately evaluated by a one compartment model?
25. What is the volume of the central compartment (L)?
26. What is the clearance of clentiazem (L/hr)?
27. What is the MRT of clentiazem (hr)?
28. What is the of clentiazem (L)?
29. What is the for clentiazem (L)?
30. What percent of the clentiazem dose is in the central compartment at equilibrium?
Table 2:
A
1
37.52ng mL
2.70hr
1
B
1
16.17ng mL
0.078hr
1
k
10 0.243hr
1
k
12 1.67hr
1
k
21 0.868hr
1
AUMC
2729.6ng mL hr
2

Vd
eff
V
Exam 3
31. What is the , and for a 20 mg IV daily dose clentiazem (ng/mL)?
32. What is the for the above dosing regimen (ng/mL)?
33. What is the for the above dosing regimen (ng/mL)?
Any number from the answer pool may be used once, more than once, or not at all.
TABLE 2-1 Answer Pool
A
B
C
D
E
F
G
H
I
J
A
B
C
D
E
F
G
H
I
J
Cp
ss
max
Cp
ss
min
Cp
ss
avg

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Basic Pharmacokinetics REV. 99.4.

Basic Pharmacokinetics REV. 99.4.25 2-68

I.V. Bolus Dosing

Patient Condition Normal Normal FRR=0.5 FIR=0.5 FRH=0.5 FIH=0.5

Practice Exams: Section 1 : Enalapril - Section 1

0.3mg = 5 1 2.25 1.45 ( ) =

Practice Exams: Section 1

Practice Exams: Section 1

Practice Exams: Section 1

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